Journal articles: 'Lysosome-associated membrane glycoproteins'

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Chen, J. W., T. L. Murphy, M. C. Willingham, I. Pastan, and J. T. August. "Identification of two lysosomal membrane glycoproteins." Journal of Cell Biology 101, no. 1 (July 1, 1985): 85–95. http://dx.doi.org/10.1083/jcb.101.1.85.

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Two murine lysosome-associated membrane proteins, LAMP-1 of 105,000-115,000 D and LAMP-2 of 100,000-110,000 D, have been identified by monoclonal antibodies that bind specifically to lysosomal membranes. Both glycoproteins were distinguished as integral membrane components solubilized by detergent solutions but not by various chaotropic agents. The lysosome localization was demonstrated by indirect immunofluorescent staining, co-localization of the antigen to sites of acridine orange uptake, and immunoelectron microscopy. Antibody binding was predominantly located at the limiting lysosomal membrane, distinctly separated from colloidal gold-labeled alpha-2-macroglobulin accumulated in the lumen during prolonged incubation. LAMP-1 and LAMP-2 also appeared to be present in low concentrations on Golgi trans-elements but were not detected in receptosomes marked by the presence of newly endocytosed alpha-2-macroglobulin, or in other cellular structures. LAMP-1 and LAMP-2 were distinguished as different molecules by two-dimensional gel analysis, 125I-tryptic peptide mapping, and sequential immunoprecipitations of 125I-labeled cell extracts. Both glycoproteins were synthesized as a precursor protein of approximately 90,000 D, and showed a marked heterogeneity of apparent molecular weight expression in different cell lines. LAMP-2 was closely related or identical to the macrophage antigen, MAC-3, as indicated by antibody adsorption and tryptic peptide mapping. It is postulated that these glycoproteins, as major protein constituents of the lysosomal membrane, have important roles in lysosomal structure and function.

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Janvier, Katy, and Juan S. Bonifacino. "Role of the Endocytic Machinery in the Sorting of Lysosome-associated Membrane Proteins." Molecular Biology of the Cell 16, no. 9 (September 2005): 4231–42. http://dx.doi.org/10.1091/mbc.e05-03-0213.

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The limiting membrane of the lysosome contains a group of transmembrane glycoproteins named lysosome-associated membrane proteins (Lamps). These proteins are targeted to lysosomes by virtue of tyrosine-based sorting signals in their cytosolic tails. Four adaptor protein (AP) complexes, AP-1, AP-2, AP-3, and AP-4, interact with such signals and are therefore candidates for mediating sorting of the Lamps to lysosomes. However, the role of these complexes and of the coat protein, clathrin, in sorting of the Lamps in vivo has either not been addressed or remains controversial. We have used RNA interference to show that AP-2 and clathrin—and to a lesser extent the other AP complexes—are required for efficient delivery of the Lamps to lysosomes. Because AP-2 is exclusively associated with plasma membrane clathrin coats, our observations imply that a significant population of Lamps traffic via the plasma membrane en route to lysosomes.

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Cieutat, A. M., P. Lobel, J. T. August, L. Kjeldsen, H. Sengeløv, N. Borregaard, and D. F. Bainton. "Azurophilic Granules of Human Neutrophilic Leukocytes Are Deficient in Lysosome-Associated Membrane Proteins but Retain the Mannose 6-Phosphate Recognition Marker." Blood 91, no. 3 (February 1, 1998): 1044–58. http://dx.doi.org/10.1182/blood.v91.3.1044.

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Abstract During granulocyte differentiation in the bone marrow (BM), neutrophilic leukocyte precursors synthesize large amounts of lysosomal enzymes. These enzymes are sequestered into azurophilic storage granules until used days later for digestion of phagocytized microorganisms after leukocyte emigration to inflamed tissues. This azurophil granule population has previously been defined as a primary lysosome, ie, a membrane-bound organelle containing acid hydrolases that have not entered into a digestive event. In this study, azurophil granules were purified and shown to contain large amounts of mannose 6-phosphate-containing glycoproteins (Man 6-P GP) but little lysosome-associated membrane proteins (LAMP). In addition, the fine structural localization of Man 6-P GP and LAMP was investigated at various stages of maturation in human BM and blood. Man 6-P GP were present within the azurophilic granules at all stages of maturation and in typical multivesicular bodies (MVB) as well as in multilaminar compartments (MLC), identified by their content of concentric arrays of internal membranes. LAMP was absent in all identified granule populations, but was consistently found in the membranes of vesicles, MVB, and MLC. The latter compartment has not been previously described in this cell type. In conclusion, the azurophilic granules, which contain an abundance of lysosomal enzymes and Man 6-P GP, lack the LAMP glycoproteins. By current criteria, they therefore cannot be classified as lysosomes, but rather may have the functional characteristics of a regulated secretory granule. Rather, the true lysosomes of the resting neutrophil are probably the MVB and MLC. Finally, the typical “dense bodies” or mature lysosomes described in other cells are not present in resting neutrophils.

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Cieutat, A. M., P. Lobel, J. T. August, L. Kjeldsen, H. Sengeløv, N. Borregaard, and D. F. Bainton. "Azurophilic Granules of Human Neutrophilic Leukocytes Are Deficient in Lysosome-Associated Membrane Proteins but Retain the Mannose 6-Phosphate Recognition Marker." Blood 91, no. 3 (February 1, 1998): 1044–58. http://dx.doi.org/10.1182/blood.v91.3.1044.1044_1044_1058.

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During granulocyte differentiation in the bone marrow (BM), neutrophilic leukocyte precursors synthesize large amounts of lysosomal enzymes. These enzymes are sequestered into azurophilic storage granules until used days later for digestion of phagocytized microorganisms after leukocyte emigration to inflamed tissues. This azurophil granule population has previously been defined as a primary lysosome, ie, a membrane-bound organelle containing acid hydrolases that have not entered into a digestive event. In this study, azurophil granules were purified and shown to contain large amounts of mannose 6-phosphate-containing glycoproteins (Man 6-P GP) but little lysosome-associated membrane proteins (LAMP). In addition, the fine structural localization of Man 6-P GP and LAMP was investigated at various stages of maturation in human BM and blood. Man 6-P GP were present within the azurophilic granules at all stages of maturation and in typical multivesicular bodies (MVB) as well as in multilaminar compartments (MLC), identified by their content of concentric arrays of internal membranes. LAMP was absent in all identified granule populations, but was consistently found in the membranes of vesicles, MVB, and MLC. The latter compartment has not been previously described in this cell type. In conclusion, the azurophilic granules, which contain an abundance of lysosomal enzymes and Man 6-P GP, lack the LAMP glycoproteins. By current criteria, they therefore cannot be classified as lysosomes, but rather may have the functional characteristics of a regulated secretory granule. Rather, the true lysosomes of the resting neutrophil are probably the MVB and MLC. Finally, the typical “dense bodies” or mature lysosomes described in other cells are not present in resting neutrophils.

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Dahlgren, C., S. R. Carlsson, A. Karlsson, H. Lundqvist, and C. Sjölin. "The lysosomal membrane glycoproteins Lamp-1 and Lamp-2 are present in mobilizable organelles, but are absent from the azurophil granules of human neutrophils." Biochemical Journal 311, no. 2 (October 15, 1995): 667–74. http://dx.doi.org/10.1042/bj3110667.

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The subcellular localization of two members of a highly glycosylated protein group present in lysosomal membranes in most cells, the lysosome-associated membrane proteins 1 and 2 (Lamp-1 and Lamp-2), was examined in human neutrophil granulocytes. Antibodies that were raised against purified Lamp-1 adn Lamp-2 gave a distinct granular staining of the cytoplasm upon immunostaining of neutrophils. Subcellular fractionation was used to separate the azurophil and specific granules from a light-membrane fraction containing plasma membranes and secretory vesicles, and Western blotting was used to determine the presence of the Lamps in these fractions. The results show that Lamp-1 and Lamp-2 are present in the specific-granule-enriched fraction and in the light-membrane fraction, but not in the azurophil granules. Separation of secretory vesicles from plasma membranes disclosed that the light-membrane Lamps were present primarily in the secretory-vesicle-enriched fraction. During phagocytosis both Lamp-1 and Lamp-2 became markedly concentrated around the ingested particle and they both appear on the cell surface when the secretory organelles are mobilized.

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Kazakova, Maria Hr, Dmitrii G. Staykov, Ilian G. Koev, Borislav D. Kitov, and Victoria S. Sarafian. "A Comparative Study Of Lamps And Ykl-40 Tissue Expression In Glial Tumors." Folia Medica 56, no. 3 (September 1, 2014): 194–98. http://dx.doi.org/10.2478/folmed-2014-0028.

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ABSTRACT INTRODUCTION: YKL-40 is a glycoprotein believed potentially to be a marker of various pathological processes. High levels of YKL-40 have been found in cancer and chronic infl ammatory diseases. The function of the glycoprotein is not completely known yet. A possible involvement in angiogenesis and tumor aggressiveness is supposed. Lysosome-associated membrane glycoproteins (LAMP) 1 and 2 are highly conserved proteins with still undefi ned biological functions. There is evidence that they are implicated in autophagy, angiogenesis and tissue remodeling. AIM: The aim of the present study was to investigate the potential relationship between the tissue expression of YKL-40, LAMP-1 and LAMP-2 in glial tumors. MATERIAL AND METHODS: LAMPs and YKL-40 expression was determined by immunohistochemistry in 36 glial tumors. A morphometric analysis of the intensity of tissue expression was performed with the Quick-photo Micro 2.3. system. Area (μm), perimeter (μm), and expression level (%) of the three glycoproteins were calculated. RESULTS: LAMPs were found on cell membranes of glial and endothelial cells, while YKL-40 was detected in the cytoplasm of these cells. Intensive immunohistochemical reaction was present in tumor cells. LAMP-2 showed a more intensive staining compared to LAMP-1. CONCLUSION: We present the fi rst comparative study of YKL-40 and LAMPs in astroglial tumors. The relationship between the expression of the three glycoconjugates indicates a possible participation in the processes of angiogenesis and tissue remodeling during tumor development

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Saftig, Paul, Bernd Schröder, and Judith Blanz. "Lysosomal membrane proteins: life between acid and neutral conditions." Biochemical Society Transactions 38, no. 6 (November 24, 2010): 1420–23. http://dx.doi.org/10.1042/bst0381420.

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Whereas we have a profound understanding about the function and biogenesis of the protein constituents in the lumen of the lysosomal compartment, much less is known about the functions of proteins of the lysosomal membrane. Proteomic analyses of the lysosomal membrane suggest that, apart from the well-known lysosomal membrane proteins, additional and less abundant membrane proteins are present. The identification of disease-causing genes and the in-depth analysis of knockout mice leading to mutated or absent membrane proteins of the lysosomal membrane have demonstrated the essential role of these proteins in lysosomal acidification, transport of metabolites resulting from hydrolytic degradation and interaction and fusion with other cellular membrane systems. In addition, trafficking pathways of lysosomal membrane proteins are closely linked to the biogenesis of this compartment. This is exemplified by the recent finding that LIMP-2 (lysosomal integral membrane protein type-2) is responsible for the mannose 6-phosphate receptor-independent delivery of newly synthesized β-glucocerebrosidase to the lysosome. Similar to LIMP-2, which could also be linked to vesicular transport processes in certain polarized cell types, the major constituents of the lysosomal membrane, the glycoproteins LAMP (lysosome-associated membrane protein)-1 and LAMP-2 are essential for regulation of lysosomal motility and participating in control of membrane fusion events between autophagosomes or phagosomes with late endosomes/lysosomes. Our recent investigations into the role of these proteins have not only increased our understanding of the endolysosomal system, but also supported their major role in cell physiology and the development of different diseases.

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Helps, C. R., and J. D. McGivan. "Regulation of glycosylation of Lamp-1 in the bovine renal epithelial cell line NBL-1 by changes in the concentration of extracellular phosphate." Biochemical Journal 303, no. 2 (October 15, 1994): 613–18. http://dx.doi.org/10.1042/bj3030613.

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We have identified the bovine renal homologue of Lamp-1 (lysosomal-associated membrane glycoprotein 1). It has very similar physical characteristics to other Lamp-1 proteins from a wide variety of tissues and species. Partial sequence analysis has shown it to be 61% identical with human Lamp-1 and about 50% identical with rat and mouse Lamp-1. The extent of glycosylation of bovine Lamp-1 alters in response to changes in the concentration of extracellular phosphate. Bovine renal epithelial cells (NBL-1) grown in normal or phosphate-starved medium contain Lamp-1 of 120 kDa. However, if cells are grown in medium containing 8-10 mM phosphate, they contain Lamp-1 of only 100 kDa. The core protein and mRNA levels have been shown to remain constant under both conditions. Therefore the only conclusion is that the extent of Lamp-1 glycosylation must be changing in response to the extracellular concentration of phosphate. Unlike Carlsson and Fukuda [(1990) J. Biol. Chem. 265, 20488-20495], who showed that the human Lamp-1 protein contained polylactosaminoglycan residues, we have been unable to demonstrate the partial deglycosylation of bovine Lamp-1 by endo-beta-galactosidase. This enzyme removes polylactosaminoglycan groups from glycoproteins, and therefore indicates that the carbohydrate structure of bovine Lamp-1 is probably different from that of other Lamp-1 proteins. At present the physiological importance of bovine renal Lamp-1 and the changes in its extent of glycosylation are unknown. In this paper we postulate that Lamp-1 may be involved in the cycling of plasma-membrane proteins to the lysosome. This is based on the finding that the only other known effect of high extracellular phosphate on NBL-1 cells is to cause a decrease in the Vmax. of plasma-membrane-associated Na(+)-dependent phosphate transport [Helps and McGivan (1991) Eur. J. Biochem. 200, 797-803].

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Clemens, Daniel L., Bai-Yu Lee, and Marcus A. Horwitz. "Francisella tularensis Phagosomal Escape Does Not Require Acidification of the Phagosome." Infection and Immunity 77, no. 5 (February 23, 2009): 1757–73. http://dx.doi.org/10.1128/iai.01485-08.

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ABSTRACT Following uptake, Francisella tularensis enters a phagosome that acquires limited amounts of lysosome-associated membrane glycoproteins and does not acquire cathepsin D or markers of secondary lysosomes. With additional time after uptake, F. tularensis disrupts its phagosomal membrane and escapes into the cytoplasm. To assess the role of phagosome acidification in phagosome escape, we followed acidification using the vital stain LysoTracker red and acquisition of the proton vacuolar ATPase (vATPase) using immunofluorescence within the first 3 h after uptake of live or killed F. tularensis subsp. holarctica live vaccine strain (LVS) by human macrophages. Whereas 90% of the phagosomes containing killed LVS stained intensely for the vATPase and were acidified, only 20 to 30% of phagosomes containing live LVS stained intensely for the vATPase and were acidified. To determine whether transient acidification might be required for phagosome escape, we assessed the impact on phagosome permeabilization of the proton pump inhibitor bafilomycin A. Using electron microscopy and an adenylate cyclase reporter system, we found that bafilomycin A did not prevent phagosomal permeabilization by F. tularensis LVS or virulent type A strains (F. tularensis subsp. tularensis strain Schu S4 and a recent clinical isolate) or by “F. tularensis subsp. novicida,” indicating that F. tularensis disrupts its phagosomal membrane by a mechanism that does not require acidification.

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Clemens, Daniel L., Bai-Yu Lee, and Marcus A. Horwitz. "Virulent and Avirulent Strains of Francisella tularensis Prevent Acidification and Maturation of Their Phagosomes and Escape into the Cytoplasm in Human Macrophages." Infection and Immunity 72, no. 6 (June 2004): 3204–17. http://dx.doi.org/10.1128/iai.72.6.3204-3217.2004.

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ABSTRACT Francisella tularensis, the agent of tularemia, is an intracellular pathogen, but little is known about the compartment in which it resides in human macrophages. We have examined the interaction of a recent virulent clinical isolate of F. tularensis subsp. tularensis and the live vaccine strain with human macrophages by immunoelectron and confocal immunofluorescence microscopy. We assessed the maturation of the F. tularensis phagosome by examining its acquisition of the lysosome-associated membrane glycoproteins (LAMPs) CD63 and LAMP1 and the acid hydrolase cathepsin D. Two to four hours after infection, vacuoles containing live F. tularensis cells acquired abundant staining for LAMPs but little or no staining for cathepsin D. However, after 4 h, the colocalization of LAMPs with live F. tularensis organisms declined dramatically. In contrast, vacuoles containing formalin-killed bacteria exhibited intense staining for all of these late endosomal/lysosomal markers at all time points examined (1 to 16 h). We examined the pH of the vacuoles 3 to 4 h after infection by quantitative immunogold staining and by fluorescence staining for lysosomotropic agents. Whereas phagosomes containing killed bacteria stained intensely for these agents, indicating a marked acidification of the phagosomes (pH 5.5), phagosomes containing live F. tularensis did not concentrate these markers and thus were not appreciably acidified (pH 6.7). An ultrastructural analysis of the F. tularensis compartment revealed that during the first 4 h after uptake, the majority of F. tularensis bacteria reside within phagosomes with identifiable membranes. The cytoplasmic side of the membranes of ∼50% of these phagosomes was coated with densely staining fibrils of ∼30 nm in length. In many cases, these coated phagosomal membranes appeared to bud, vesiculate, and fragment. By 8 h after infection, the majority of live F. tularensis bacteria lacked any ultrastructurally discernible membrane separating them from the host cell cytoplasm. These results indicate that F. tularensis initially enters a nonacidified phagosome with LAMPs but without cathepsin D and that the phagosomal membrane subsequently becomes morphologically disrupted, allowing the bacteria to gain direct access to the macrophagic cytoplasm. The capacity of F. tularensis to alter the maturation of its phagosome and to enter the cytoplasm is likely an important element of its capacity to parasitize macrophages and has major implications for vaccine development.

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Kannan, Krishnaswamy, Ruby M. Stewart, Walter Bounds, Sven R. Carlsson, Minoru Fukuda, Kenneth W. Betzing, and Randall F. Holcombe. "Lysosome-Associated Membrane Proteins h-LAMP1 (CD107a) and h-LAMP2 (CD107b) Are Activation-Dependent Cell Surface Glycoproteins in Human Peripheral Blood Mononuclear Cells Which Mediate Cell Adhesion to Vascular Endothelium." Cellular Immunology 171, no. 1 (July 1996): 10–19. http://dx.doi.org/10.1006/cimm.1996.0167.

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De Souza Leao, S., T. Lang, E. Prina, R. Hellio, and J. C. Antoine. "Intracellular Leishmania amazonensis amastigotes internalize and degrade MHC class II molecules of their host cells." Journal of Cell Science 108, no. 10 (October 1, 1995): 3219–31. http://dx.doi.org/10.1242/jcs.108.10.3219.

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In their amastigote stage, Leishmania live in mammalian macrophages within parasitophorous vacuoles (PV), organelles of phagolysosomal origin that, in macrophages activated with IFN-gamma, contain major histocompatibility complex (MHC) class II molecules apparently devoid of invariant chains. We have now studied the fate of PV-associated class II molecules in mouse bone marrow-derived macrophages infected with L. amazonensis amastigotes using immunocytochemical and biochemical approaches. We have found that at least a part of these class II molecules was internalized by amastigotes and reached structures very often located in their posterior poles. This process was much more obvious if infected macrophages were incubated with protease inhibitors like antipain, chymostatin, Z-Phe-AlaCHN2 and Z-Phe-PheCHN2, or if amastigotes were pre-treated with the irreversible cysteine protease inhibitor Z-Phe-AlaCHN2 before infection, clearly indicating that amastigotes also degraded the internalized class II molecules. Study of infected macrophage cryosections by immuno-electron microscopy allowed the identification of the class II-positive structures in amastigotes as the lysosome-like organelles known as megasomes. Other PV membrane components like the prelysosomal/lysosomal glycoproteins Igp110, Igp120 and macrosialin could not be detected in megasomes of amastigotes even after treatment of macrophages with protease inhibitors, suggesting the involvement of some specific mechanism(s) for the internalization of class II molecules. Interestingly, after treatment of infected macrophages with various protease inhibitors (antipain, leupeptin, E-64, Z-Phe-AlaCHN2, Z-Phe-PheCHN2), PV membrane as well as megasomes of amastigotes become positive for invariant chains. A quantitative analysis of amastigote-associated class II molecules based on enzyme immunoassays showed that: (a) amastigotes extracted from macrophages treated with both IFN-gamma and antipain or Z-Phe-AlaCHN2 contained a much greater amount of class II than amastigotes extracted from macrophages treated with IFN-gamma alone; (b) class II molecules associated with the former were mainly intracellular and, at least some of them, were complexed with invariant chains or fragments of invariant chains; (c) amastigotes pre-incubated with Z-Phe-AlaCHN2 before infection accumulated a greater amount of intracellular class II than amastigotes pre-incubated without inhibitor, clearly indicating that the blockade of parasite cysteine proteases was sufficient to enhance the pool of these molecules within megasomes. On the whole, these data are consistent with the idea that class II molecules reaching PV are newly synthesized and still complexed with intact invariant chains or with partially degraded invariant chains.(ABSTRACT TRUNCATED AT 400 WORDS)

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Wang, Di, Xuemin Cao, Yuquan Zhang, Yuanlin Liu, Chan Yao, Wenliang Ge, and Yunzhao Xu. "LAMP3 expression correlated with poor clinical outcome in human ovarian cancer." Tumor Biology 39, no. 3 (March 2017): 101042831769501. http://dx.doi.org/10.1177/1010428317695014.

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Lysosome-associated membrane protein 3 belongs to the lysosome-associated membrane glycoprotein family, which is associated with lymph node, metastasis, poor overall survival, and resistance to chemotherapy and radiotherapy. Epithelial ovarian cancer is one of the most deadly global female gynecologic malignant tumors. Its clinical outcome is poor and most epithelial ovarian cancer patients tend to relapse because of drug resistance. However, lysosome-associated membrane protein 3 expression in epithelial ovarian cancer and its relationship between clinicopathologic factors remain poorly understood. To clarify the prognostic implications of lysosome-associated membrane protein 3 in epithelial ovarian cancer, we analyzed both messenger RNA and protein levels of lysosome-associated membrane protein 3 in ovarian carcinomas. Polymerase chain reaction results showed higher expression of lysosome-associated membrane protein 3 messenger RNA in epithelial ovarian cancer than in noncancerous tissues. Immunohistochemical results showed that high lysosome-associated membrane protein 3 cytoplasmic expression was significantly related to tumor grade ( p = 0.038), lymph node metastasis ( p = 0.049), metastasis ( p < 0.001), level of CA125 ( p = 0.030), and International Federation of Gynecology and Obstetrics (FIGO) ( p < 0.001). High lysosome-associated membrane protein 3 nuclear expression was significantly associated with tumor grade ( p = 0.046), tumor single or double (representative whether the tumor involving one or both ovaries) ( p = 0.016), metastasis ( p < 0.001), and FIGO stage ( p < 0.001). Survival analysis indicated that high lysosome-associated membrane protein 3 cytoplasmic expression (hazard ratio: 4.632, 95% confidence interval: 2.421–8.864; p < 0.001), patients’ age (hazard ratio: 1.729, 95% confidence interval: 1.027–2.911; p = 0.039), and FIGO stage (hazard ratio: 2.049, 95% confidence interval: 1.113–3.774; p = 0.021) were significantly correlated with poor survival outcome of epithelial ovarian cancer patients.

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Silverstein, RL, and M. Febbraio. "Identification of lysosome-associated membrane protein-2 as an activation-dependent platelet surface glycoprotein." Blood 80, no. 6 (September 15, 1992): 1470–75. http://dx.doi.org/10.1182/blood.v80.6.1470.1470.

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Abstract Platelets undergo biochemical and morphologic changes when stimulated that greatly alter their function and contribute to their role in thrombosis and hemostasis. We recently identified and cloned the cDNA for a platelet surface glycoprotein expressed on activated, not resting cells. We found that this protein, lysome-associated membrane protein-1 (LAMP-1), is an integral membrane protein of the lysosome that translocated to the surface membrane when platelets were stimulated by a strong agonist. We now show with immunofluorescence flow cytometry that LAMP-2, a lysosomal membrane protein that shares approximately 30% homology with LAMP-1, is also expressed preferentially on the surface of activated platelets. Equilibrium binding studies with 125I-anti-LAMP- 2 IgG showed approximately 1,100 binding sites per thrombin-stimulated platelet and less than 50 per resting platelet. Sucrose gradient ultracentrifugation fractionation of resting platelet sonicates showed that LAMP-2 colocalized with LAMP-1 and with lysosomal enzymes, and not with thrombospondin or serotonin, which are markers of the two other platelet granule compartments, alpha-granules and dense granules. LAMP- 2 surface expression was minimal in response to platelet stimulation by weak agonists such as epinephrine and ADP. These data show that LAMP-2, like LAMP-1, translocates from the lysosomal membrane compartment to the surface membrane when platelets are activated. Regulated surface expression of these heavily glycosylated proteins may play a role in the adhesive, prothrombotic phenotype of these cells.

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Silverstein, RL, and M. Febbraio. "Identification of lysosome-associated membrane protein-2 as an activation-dependent platelet surface glycoprotein." Blood 80, no. 6 (September 15, 1992): 1470–75. http://dx.doi.org/10.1182/blood.v80.6.1470.bloodjournal8061470.

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Platelets undergo biochemical and morphologic changes when stimulated that greatly alter their function and contribute to their role in thrombosis and hemostasis. We recently identified and cloned the cDNA for a platelet surface glycoprotein expressed on activated, not resting cells. We found that this protein, lysome-associated membrane protein-1 (LAMP-1), is an integral membrane protein of the lysosome that translocated to the surface membrane when platelets were stimulated by a strong agonist. We now show with immunofluorescence flow cytometry that LAMP-2, a lysosomal membrane protein that shares approximately 30% homology with LAMP-1, is also expressed preferentially on the surface of activated platelets. Equilibrium binding studies with 125I-anti-LAMP- 2 IgG showed approximately 1,100 binding sites per thrombin-stimulated platelet and less than 50 per resting platelet. Sucrose gradient ultracentrifugation fractionation of resting platelet sonicates showed that LAMP-2 colocalized with LAMP-1 and with lysosomal enzymes, and not with thrombospondin or serotonin, which are markers of the two other platelet granule compartments, alpha-granules and dense granules. LAMP- 2 surface expression was minimal in response to platelet stimulation by weak agonists such as epinephrine and ADP. These data show that LAMP-2, like LAMP-1, translocates from the lysosomal membrane compartment to the surface membrane when platelets are activated. Regulated surface expression of these heavily glycosylated proteins may play a role in the adhesive, prothrombotic phenotype of these cells.

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Zhou, Bao-Kang, Raymond E. Boissy, Sharon Pifko-Hirst, Denis J. Moran, and Seth J. Orlow. "Lysosome-Associated Membrane Protein-1 (LAMP-1) Is the Melanocyte Vesicular Membrane Glycoprotein Band II." Journal of Investigative Dermatology 100, no. 2 (February 1993): 110–14. http://dx.doi.org/10.1111/1523-1747.ep12462775.

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D'Souza, M. Patricia, and J. Thomas August. "A kinetic analysis of biosynthesis and localization of a lysosome-associated membrane glycoprotein." Archives of Biochemistry and Biophysics 249, no. 2 (September 1986): 522–32. http://dx.doi.org/10.1016/0003-9861(86)90030-5.

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CHANG, Melissa H. Y., Chi T. HUA, Elizabeth L. ISAAC, Tom LITJENS, Greg HODGE, Litsa E. KARAGEORGOS, and Peter J. MEIKLE. "Transthyretin interacts with the lysosome-associated membrane protein (LAMP-1) in circulation." Biochemical Journal 382, no. 2 (August 24, 2004): 481–89. http://dx.doi.org/10.1042/bj20031752.

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LAMP-1 (lysosome-associated membrane protein), a major glycoprotein present in the lysosomal membrane, constitutes up to 50% of total membrane proteins. LAMP-1, expressed at the plasma membrane, is reported to be the major molecule expressing the sialyl-Lewis X antigen. Two forms of LAMP-1 exist; the full-length LAMP-1 [LAMP-1 (+Tail)] has a highly glycosylated lumenal domain, a membrane-spanning domain and a short cytoplasmic tail, and the truncated LAMP-1 [LAMP-1 (−Tail)] contains only the lumenal domain. Soluble LAMP-1 (±Tail) has been reported in circulation. LAMP-1 at the cell surface has been shown to interact with E-selectin and galectin and is proposed to function in cell–cell interactions. However, the functional role(s) of soluble LAMP-1 in circulation is unclear. To investigate the functional role of soluble LAMP-1 in circulation, recombinant LAMP-1 (−Tail) and LAMP-1 (+Tail) were produced in HT1080 cells. Two immune-quantification assays were developed to distinguish between the LAMP-1 forms. The interaction and aggregation properties of the different LAMP-1 forms were investigated using the immune-quantification assays. Only LAMP-1 (+Tail) was found to aggregate and interact with plasma proteins. Plasma proteins that interact with LAMP-1 were isolated by affinity chromatography with either the recombinant LAMP-1 (−Tail) or a synthesized peptide consisting of the 14 amino acids of the LAMP-1 cytoplasmic tail. Transthyretin was found to interact with the cytoplasmic tail of LAMP-1. Transthyretin exists as a homotetramer in plasma, as such may play a role in the aggregation of LAMP-1 in circulation.

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HOGUE, Douglas L., Colin NASH, Victor LING, and Tom C. HOBMAN. "Lysosome-associated protein transmembrane 4α (LAPTM4α) requires two tandemly arranged tyrosine-based signals for sorting to lysosomes." Biochemical Journal 365, no. 3 (August 1, 2002): 721–30. http://dx.doi.org/10.1042/bj20020205.

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Lysosome-associated protein transmembrane 4α (LAPTM4α) and homologues comprise a family of conserved proteins, which are found in mammals, insects and nematodes. LAPTM4α functions to regulate the intracellular compartmentalization of amphipathic solutes and possibly the sensitivity of cells toward anthracyclines, antibiotics, ionophores, nucleobases and organic cations. This is similar to the multidrug-resistance phenotype exhibited by cells synthesizing high levels of P-glycoprotein. Accordingly, it is possible that LAPTM4α may be a suitable target for development of novel chemotherapeutic agents. LAPTM4α contains four putative membrane-spanning domains and a 55 amino acid C-terminal region that faces the cytoplasm. Localization of LAPTM4α to endosomes and lysosomes appears to be tightly controlled as transient high-level expression of LAPTM4α in cultured cells resulted in no detectable protein on the cell surface. Mutagenic analysis of the C-terminus of LAPTM4α indicated that two tandomly arranged tyrosine-containing motifs in the cytoplasmic domain are required for efficient localization of LAPTM4α to vesicles containing the lysosomal marker lysosomal glycoprotein 120. Although a number of membrane proteins that localize to endosomes/lysosomes contain more than one independently functioning sorting signal, to our knowledge, LAPTM4α is the first example of a membrane protein that requires two tandemly arranged tyrosine-based sorting signals for efficient localization in these compartments.

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Lingnau, A., R. Zufferey, M. Lingnau, and D. G. Russell. "Characterization of tGLP-1, a Golgi and lysosome-associated, transmembrane glycoprotein of African trypanosomes." Journal of Cell Science 112, no. 18 (September 15, 1999): 3061–70. http://dx.doi.org/10.1242/jcs.112.18.3061.

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Purification of endosomal/lysosomal vesicles of Trypanosoma brucei brucei bloodstream forms and generation of monoclonal antibodies led to the isolation of antibodies directed against an 85 kDa, Golgi and endocytic traffic-associated protein termed tGLP-1, Trypanosoma Golgi/lysosome protein-1. Preliminary immunoelectron microscopical analysis revealed that the protein is present in, but not restricted to, the limiting membrane of multivesicular lysosomes and is more abundant in bloodstream forms compared to the procyclic stage. The corresponding gene was cloned and is present as a single copy. Blast searches did not reveal any homologies to other proteins and genes published. The nucleotide sequence of the gene (1848 base pairs) predicted a type 1 membrane topology with an N-terminal signal sequence (20 aa), a luminal domain with 2 N-glycosylation sites (524 aa), a transmembrane domain (23 aa), and a long cytosolic tail domain (49 aa). Polyclonal antibodies raised against the cytosolic tail confirmed the localization of the gene product to multivesicular lysosomes but revealed that the majority of the protein was in the Golgi apparatus. Colabelling with an antibody against p67, a lysosomal glycoprotein of trypanosomes, revealed extensive overlap between the proteins with opposing relative abundance. Expression of the tGLP-1 open reading frame in Leishmania resulted in Golgi localization, and in Toxoplasma, in localization to both the Golgi and endoplasmic reticulum. These data indicate conservation in the functionality of the Golgi-targeting sequence of tGLP-1.

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Martínez-Menárguez, J. A., H. J. Geuze, and J. Ballesta. "Evidence for a nonlysosomal origin of the acrosome." Journal of Histochemistry & Cytochemistry 44, no. 4 (April 1996): 313–20. http://dx.doi.org/10.1177/44.4.8601690.

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We studied the biogenesis of the acrosome in sperm cells in immunogold-labeled ultrathin cryosections of rat testis, using a variety of antibodies against endosomal/lysosomal marker protein and acrosin, the major secretory protein of sperm cells. As expected, acrosomes and proacrosomal vesicles in the trans-Golgi region contained abundant acrosin. Rat lysosomal membrane glycoprotein (lgp) 120 and mouse lysosome-associated membrane protein-1 were not detectable in the acrosomal membrane. Similarly, the late endosomal markers cation-dependent and -independent mannose 6-phosphate receptors were absent from the acrosome and proacrosomal vesicles. Therefore, acrosomes do not exhibit these endosomal/lysosomal features. Apart from (pro) acrosomal vesicles, both spermatocytes and spermatids contained classical lysosomes (positive for rat lgp 120, mouse lysosome-associated membrane protein-1, and cathepsin D) that were negative for acrosin. Quantitative analysis of the immunogold labeling showed that spermatocytes express more mannose 6-phosphate receptors and lgp 120 than spermatids, whereas the opposite situation existed for acrosin. These data indicate differential synthetic activity of lysosomal and acrosomal constituents in different states of sperm differentiation. Together, our observations argue against a lysosomal /endosomal origin of the acrosome.

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Liu, Yang, Baozeng Sun, Jingyu Pan, Yuancai Feng, Wei Ye, Jiahao Xu, Mingfu Lan, et al. "Construction and evaluation of DNA vaccine encoding Ebola virus glycoprotein fused with lysosome-associated membrane protein." Antiviral Research 193 (September 2021): 105141. http://dx.doi.org/10.1016/j.antiviral.2021.105141.

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Hopper, Sylvia, Brandi Vasquez, Alex Merz, Susan Clary, J. Scott Wilbur, and Magdalene So. "Effects of the Immunoglobulin A1 Protease on Neisseria gonorrhoeae Trafficking across Polarized T84 Epithelial Monolayers." Infection and Immunity 68, no. 2 (February 1, 2000): 906–11. http://dx.doi.org/10.1128/iai.68.2.906-911.2000.

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ABSTRACT We previously demonstrated that the Neisseria IgA1 protease cleaves LAMP1 (lysosome-associated membrane protein 1), a major integral membrane glycoprotein of lysosomes, thereby accelerating its degradation rate in infected A431 human epidermoid carcinoma cells and resulting in the alteration of lysosomes in these cells. In this study, we determined whether the IgA1 protease also affects the trafficking of Neisseria gonorrhoeae across polarized T84 epithelial monolayers. We report that N. gonorrhoeaeinfection of T84 monolayers, grown on a solid substrate or polarized on semiporous membranes, also results in IgA1 protease-mediated reduction of LAMP1. We demonstrate that iga mutants in two genetic backgrounds exited polarized T84 monolayers in fewer numbers than the corresponding wild-type strains. Finally, we present evidence that these mutants have a statistically significant and reproducible defect in their ability to traverse T84 monolayers. These results add to our previous data by showing that the IgA1 protease alters lysosomal content in polarized as well as unpolarized cells and by demonstrating a role for the protease in the traversal of epithelial barriers by N. gonorrhoeae.

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Rizzolo, L. J., J. Finidori, A. Gonzalez, M. Arpin, I. E. Ivanov, M. Adesnik, and D. D. Sabatini. "Biosynthesis and intracellular sorting of growth hormone-viral envelope glycoprotein hybrids." Journal of Cell Biology 101, no. 4 (October 1, 1985): 1351–62. http://dx.doi.org/10.1083/jcb.101.4.1351.

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Various aspects of the biogenetic mechanisms that are involved in the insertion of nascent plasma membrane proteins into the endoplasmic reticulum (ER) membrane and their subsequent distribution through the cell have been investigated. For these studies chimeric genes that encode hybrid proteins containing carboxy-terminal portions of the influenza virus hemagglutinin (154 amino acids) or the vesicular stomatitis virus envelope glycoprotein (G) (60 amino acids) linked to the carboxy terminus of a nearly complete secretory polypeptide, growth hormone (GH), were used. In in vitro transcription-translation experiments, it was found that the insertion signal in the GH portion of the chimeras led to incorporation of the membrane protein segments into the ER membrane. Effectively, GH became part of the luminal segment of membrane proteins of which only very small segments, corresponding to the cytoplasmic portions of the G or HA proteins, remained exposed on the surface of the microsomes. When the chimeric genes were expressed in transfected cells, the products, as expected, failed to be secreted and remained cell-associated. These results support the assignment of a halt transfer role to segments of the membrane polypeptides that include their transmembrane portions. The hybrid polypeptide containing the carboxy-terminal portion of HA linked to GH accumulated in a juxtanuclear region of the cytoplasm within modified ER cisternae, closely apposed to the Golgi apparatus. The location and appearance of these cisternae suggested that they represent overdeveloped transitional ER elements and thus may correspond to a natural way station between the ER and the Golgi apparatus, in which further transfer of the artificial molecules is halted. The GH-G hybrid could only be detected in transfected cells treated with chloroquine, a drug that led to its accumulation in the membranes of endosome or lysosome-like cytoplasmic vesicles. Although the possibility that the chimeric protein entered such vesicles directly from the Golgi apparatus cannot be ruled out, it appears more likely that it was first transferred to the cell surface and was then internalized by endocytosis.

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Jiang, Dong-Bo, Yuan-Jie Sun, Lin-Feng Cheng, Ge-Fei Zhang, Chen Dong, Bo-Quan Jin, Chao-Jun Song, Ying Ma, Fang-Lin Zhang, and Kun Yang. "Construction and evaluation of DNA vaccine encoding Hantavirus glycoprotein N-terminal fused with lysosome-associated membrane protein." Vaccine 33, no. 29 (June 2015): 3367–76. http://dx.doi.org/10.1016/j.vaccine.2015.05.007.

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26

Kirschner, Andreas, Melanie Thiede, Franziska Blaeschke, Günther H. S. Richter, Julia S. Gerke, Michaela C. Baldauf, Thomas G. P. Grünewald, Dirk H. Busch, Stefan Burdach, and Uwe Thiel. "Lysosome-associated membrane glycoprotein 1 predicts fratricide amongst T cell receptor transgenic CD8+ T cells directed against tumor-associated antigens." Oncotarget 7, no. 35 (July 18, 2016): 56584–97. http://dx.doi.org/10.18632/oncotarget.10647.

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27

Zhou, Zhuo, Qinghua Xue, Yuli Wan, Yaowu Yang, Jianwei Wang, and Tao Hung. "Lysosome-associated membrane glycoprotein 3 is involved in influenza A virus replication in human lung epithelial (A549) cells." Virology Journal 8, no. 1 (2011): 384. http://dx.doi.org/10.1186/1743-422x-8-384.

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Akasaki, Kenji, Yasonori Yamaguchi, Koji Furuno, and Hiroshi Tsuji. "Purification, Some Properties, and Tissue Distribution of a Major Lysosome-Associated Membrane Glycoprotein (r-lamp-2) of Rat Liver." Journal of Biochemistry 110, no. 6 (December 1991): 922–27. http://dx.doi.org/10.1093/oxfordjournals.jbchem.a123690.

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Deng, Y. P., G. Griffiths, and B. Storrie. "Comparative behavior of lysosomes and the pre-lysosome compartment (PLC) in in vivo cell fusion experiments." Journal of Cell Science 99, no. 3 (July 1, 1991): 571–82. http://dx.doi.org/10.1242/jcs.99.3.571.

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Interspecies cell fusion was used to compare protein intermixing within the mannose 6-phosphate receptor (MPR)-enriched pre-lysosome compartment (PLC) and within the MPR-negative lysosomal compartment. Both compartments were positive for lysosomal glycoprotein (lgp) membrane markers but were morphologically distinct. In most experiments, rat-mouse cell syncytia were formed by u.v.-inactivated Sindbis virus-mediated fusion. By immunogold electron microscopy of syncytia, extensive intermixing of species-specific lysosomal membrane proteins was observed in both lysosomes and PLC. At 3 h post cell fusion, multiple-label immunogold studies showed that 82% of the lysosome-like structures positive for the rat lysosomal membrane protein LIMP-I were also positive for the mouse lysosomal membrane protein mLAMP-1. By immunofluorescence, LIMP-I and mLAMP-1 co-localized with a t1/2 of 30 min after cell fusion; although the lgp-positive organelle populations had evidently interchanged their proteins, the lysosomal structures remained small, punctate bodies distributed throughout the syncytoplasm as observed in single cells. In contrast, the initially separate units of the PLC congregated with a t1/2 of 1 h to form large, pre-lysosome complexes associated with individual nuclear clusters. At the electron-microscope level, gold markers endocytized by the rat and mouse parent cells in a 1 h uptake followed by a 16–20 h chase co-localized in these extended PLC complexes, as did the membrane markers mLAMP-1 and LIMP-I. The density of labeling for rat MPR in the extended PLCs was markedly decreased, consistent with membrane fusions and dilution of the antigen upon congregation of the PLC compartments from the donor cells. The extended PLC complex behaved as a late endocytic compartment, as shown by co-localization of the MPR and rhodamine-dextran following a 10 min dextran uptake and a 50 min chase. These differences in behavior between lysosomes and the PLC in rat-mouse cell syncytia suggest that the pathway(s) of protein intermixing with respect to the two organelles may be different.

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Boissy, Ying L., Seth J. Orlow, and Raymond E. Boissy. "Histochemical and immunocytochemical ultrastructural localization of melanocyte specific proteins." Proceedings, annual meeting, Electron Microscopy Society of America 51 (August 1, 1993): 402–3. http://dx.doi.org/10.1017/s0424820100147843.

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Melanin synthesis in melanocytes is localized to melanosomes, where enzymatic and structural gene products must be targeted. Some gene products are translocated through different pathways (i.e., tyrosinase travels through the Golgi apparatus during processing, whereas a putative matrix glycoprotein does not). To visualize trafficking routes, we used post-embedding immunocytochemistry to compliment DOPA-histochemistry. We report on the localization of tyrosinase, matrix glycoprotein, tyrosinase-related protein 1 (TRP-1) and lysosome-associated membrane protein-1 (LAMP-1).DOPA histochemistry: Cultured melanoma cells were fixed in half-strength Karnovsky’s, incubated in 0.1 % 1-DOPA 2X for 2.5 h and embedded in Eponate 12. For immunocytochemistry, cells were fixed with 4% paraformaldehyde, 1% glutaraldehyde, and 0.2% picric acid with 0.5 mM CaCl2 (pH 7.4) for 20 m at RT, quenched in 50 mM NH4Cl for 20 m at 0°C, washed in 0.1 M maleate buffer (pH 6.5), and treated with 2% uranyl acetate (pH 4.0) for 30 m at 0°C.

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de Saint-Vis, B., J. Vincent, S. Vandenabeele, B. Vanbervliet, J. J. Pin, S. Aït-Yahia, S. Patel, et al. "A Novel Lysosome-Associated Membrane Glycoprotein, DC-LAMP, Induced upon DC Maturation, Is Transiently Expressed in MHC Class II Compartment." Immunity 9, no. 3 (September 1998): 325–36. http://dx.doi.org/10.1016/s1074-7613(00)80615-9.

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Akasaki, Kenji, and Hiroshi Tsuji. "Purification and characterization of a soluble form of lysosome-associated membrane glycoprotein-2 (lamp-2) from rat liver lysosomal contents." IUBMB Life 46, no. 1 (September 1998): 197–206. http://dx.doi.org/10.1080/15216549800203702.

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Hariri, Mehrdad, Ghania Millane, Marie-Pierre Guimond, Ginette Guay, James W. Dennis, and Ivan R. Nabi. "Biogenesis of Multilamellar Bodies via Autophagy." Molecular Biology of the Cell 11, no. 1 (January 2000): 255–68. http://dx.doi.org/10.1091/mbc.11.1.255.

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Transfection of Mv1Lu mink lung type II alveolar cells with β1–6-N-acetylglucosaminyl transferase V is associated with the expression of large lysosomal vacuoles, which are immunofluorescently labeled for the lysosomal glycoprotein lysosomal-associated membrane protein-2 and the β1–6-branchedN-glycan-specific lectin phaseolis vulgaris leucoagglutinin. By electron microscopy, the vacuoles present the morphology of multilamellar bodies (MLBs). Treatment of the cells with the lysosomal protease inhibitor leupeptin results in the progressive transformation of the MLBs into electron-dense autophagic vacuoles and eventual disappearance of MLBs after 4 d of treatment. Heterologous structures containing both membrane lamellae and peripheral electron-dense regions appear 15 h after leupeptin addition and are indicative of ongoing lysosome–MLB fusion. Leupeptin washout is associated with the formation after 24 and 48 h of single or multiple foci of lamellae within the autophagic vacuoles, which give rise to MLBs after 72 h. Treatment with 3-methyladenine, an inhibitor of autophagic sequestration, results in the significantly reduced expression of multilamellar bodies and the accumulation of inclusion bodies resembling nascent or immature autophagic vacuoles. Scrape-loaded cytoplasmic FITC-dextran is incorporated into lysosomal-associated membrane protein-2–positive MLBs, and this process is inhibited by 3-methyladenine, demonstrating that active autophagy is involved in MLB formation. Our results indicate that selective resistance to lysosomal degradation within the autophagic vacuole results in the formation of a microenvironment propicious for the formation of membrane lamella.

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Wen, Zhuoyu, Hui Li, and Juan Zhang. "The expression and clinical significance of murine double minute 2, lysosome-associated membrane protein 1, and P-glycoprotein in pediatric acute lymphoblastic leukemia." Translational Pediatrics 9, no. 5 (October 2020): 677–85. http://dx.doi.org/10.21037/tp-20-307.

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Lunding, Lars P., Daniel Krause, Guido Stichtenoth, Cordula Stamme, Niklas Lauterbach, Jan Hegermann, Matthias Ochs, et al. "LAMP3 deficiency affects surfactant homeostasis in mice." PLOS Genetics 17, no. 6 (June 23, 2021): e1009619. http://dx.doi.org/10.1371/journal.pgen.1009619.

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Lysosome-associated membrane glycoprotein 3 (LAMP3) is a type I transmembrane protein of the LAMP protein family with a cell-type-specific expression in alveolar type II cells in mice and hitherto unknown function. In type II pneumocytes, LAMP3 is localized in lamellar bodies, secretory organelles releasing pulmonary surfactant into the extracellular space to lower surface tension at the air/liquid interface. The physiological function of LAMP3, however, remains enigmatic. We generated Lamp3 knockout mice by CRISPR/Cas9. LAMP3 deficient mice are viable with an average life span and display regular lung function under basal conditions. The levels of a major hydrophobic protein component of pulmonary surfactant, SP-C, are strongly increased in the lung of Lamp3 knockout mice, and the lipid composition of the bronchoalveolar lavage shows mild but significant changes, resulting in alterations in surfactant functionality. In ovalbumin-induced experimental allergic asthma, the changes in lipid composition are aggravated, and LAMP3-deficient mice exert an increased airway resistance. Our data suggest a critical role of LAMP3 in the regulation of pulmonary surfactant homeostasis and normal lung function.

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Notomi, Shoji, Kenji Ishihara, Nikolaos E. Efstathiou, Jong-Jer Lee, Toshio Hisatomi, Takashi Tachibana, Eleni K. Konstantinou, et al. "Genetic LAMP2 deficiency accelerates the age-associated formation of basal laminar deposits in the retina." Proceedings of the National Academy of Sciences 116, no. 47 (November 7, 2019): 23724–34. http://dx.doi.org/10.1073/pnas.1906643116.

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The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the Lamp2 gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch’s membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD—namely, the accumulation of APOE, APOA1, clusterin, and vitronectin—adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch’s membrane were reduced in Lamp2 knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.

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Sauter, Birthe, Matthew L. Albert, Loise Francisco, Marie Larsson, Selin Somersan, and Nina Bhardwaj. "Consequences of Cell Death." Journal of Experimental Medicine 191, no. 3 (February 7, 2000): 423–34. http://dx.doi.org/10.1084/jem.191.3.423.

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Cell death by necrosis is typically associated with inflammation, in contrast to apoptosis. We have identified additional distinctions between the two types of death that occur at the level of dendritic cells (DCs) and which influence the induction of immunity. DCs must undergo changes termed maturation to act as potent antigen-presenting cells. Here, we investigated whether exposure to apoptotic or necrotic cells affected DC maturation. We found that immature DCs efficiently phagocytose a variety of apoptotic and necrotic tumor cells. However, only exposure to the latter induces maturation. The mature DCs express high levels of the DC-restricted markers CD83 and lysosome-associated membrane glycoprotein (DC-LAMP) and the costimulatory molecules CD40 and CD86. Furthermore, they develop into powerful stimulators of both CD4+ and CD8+ T cells. Cross-presentation of antigens to CD8+ T cells occurs after uptake of apoptotic cells. We demonstrate here that optimal cross-presentation of antigens from tumor cells requires two steps: phagocytosis of apoptotic cells by immature DCs, which provides antigenic peptides for major histocompatibility complex class I and class II presentation, and a maturation signal that is delivered by exposure to necrotic tumor cells, their supernatants, or standard maturation stimuli, e.g., monocyte-conditioned medium. Thus, DCs are able to distinguish two types of tumor cell death, with necrosis providing a control that is critical for the initiation of immunity.

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Yedgar, S., O. Eidelman, E. Malden, D. Roberts, R. Etcheberrigaray, G. Goping, C. Fox, and H. B. Pollard. "Cyclic AMP-independent secretion of mucin by SW1116 human colon carcinoma cells. Differential control by Ca2+ ionophore A23187 and arachidonic acid." Biochemical Journal 283, no. 2 (April 15, 1992): 421–26. http://dx.doi.org/10.1042/bj2830421.

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The regulation of mucin secretion by SW1116 human colon carcinoma cells has been studied using monoclonal antibody 19-9, which has previously been used to detect mucin in the serum of cancer and cystic fibrosis patients. We found that SW1116 cells constitutively secrete considerable amounts of mucin as the predominant glycoprotein. The secretion of mucin by these cells is independent of cyclic AMP levels, but can be further stimulated by the Ca2+ ionophore A23187. However, arachidonic acid and its metabolites inhibit mucin secretion. Electron microscope studies reveal that the mucin is located near the plasma membrane as well as in vesicular and lysosome-like structures. However, the secretion pathway of mucin is different than that of the lysosomal contents, since arachidonic acid, while inhibiting mucin secretion, actually activates the secretion of the lysosomal enzyme beta-glucuronidase. We suggest that the mechanism of mucin secretion by SW1116 cells occurs by a pathway different from common exocytosis, and possibly by more than one pathway. The response of mucin secretion by SW1116 cells to common secretagogues resembles that of epithelial cells obtained from cystic fibrosis patients. Thus SW1116 cells are an especially interesting system for studying processes related to pathological states associated with excessive constitutive secretion of mucin.

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Parks, Alexandre, Xavier Charest-Morin, Michael Boivin-Welch, Johanne Bouthillier, and Francois Marceau. "Autophagic flux inhibition and lysosomogenesis ensuing cellular capture and retention of the cationic drug quinacrine in murine models." PeerJ 3 (October 6, 2015): e1314. http://dx.doi.org/10.7717/peerj.1314.

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The proton pump vacuolar (V)-ATPase is the driving force that mediates the concentration of cationic drugs (weak bases) in the late endosome-lysosome continuum; secondary cell reactions include the protracted transformation of enlarged vacuoles into autophagosomes. We used the inherently fluorescent tertiary amine quinacrine in murine models to further assess the accumulation and signaling associated with cation trapping. Primary fibroblasts concentrate quinacrine ∼5,000-fold from their culture medium (KM9.8 µM; transport studies). The drug is present in perinuclear granules that are mostly positive for Rab7 and LAMP1 (microscopy). Both drug uptake and retention are extensively inhibited by treatments with the V-ATPase inhibitor bafilomycin A1. The H+ionophore monensin also prevented quinacrine concentration by fibroblasts. However, inhibition of plasma membrane transporters or of the autophagic process with spautin-1 did not alter quinacrine transport parameters. Ancillary experiments did not support that low micromolar concentrations of quinacrine are substrates for organic cation transporters-1 to -3 or P-glycoprotein. The secondary autophagy induced by quinacrine in cells may derive from the accumulation of incompetent autophagolysosomes, as judged from the accumulation of p62/SQSTM1 and LC3 II (immunoblots). Accordingly, protracted lysosomogenesis is evidenced by increased expression of LAMP1 and LAMP2 in quinacrine-treated fibroblasts (48 h, immunoblots), a response that follows the nuclear translocation of the lysosomal genesis transcription factor TFEB and upregulation of LAMP1 and −2 mRNAs (24 h). Quinacrine administration to live mice evidenced variable distribution to various organs and heterogeneous accumulation within the lung (stereo-microscopy, extraction). Dose-dependentin vivoautophagic and lysosomal accumulation was observed in the lung (immunoblots). No evidence has been found for transport or extrusion mechanisms modulating the cellular uptake of micromolar quinacrine at the plasma membrane level. As shownin vitroandin vivo, V-ATPase-mediated cation sequestration is associated, above a certain threshold, to autophagic flux inhibition and feed-back lysosomogenesis.

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Hansson, Malin, Malin Sundquist, Susanne Hering, B. Samuel Lundin, Michael Hermansson, and Marianne Quiding-Järbrink. "DC-LAMP+Dendritic Cells Are Recruited to Gastric Lymphoid Follicles in Helicobacter pylori-Infected Individuals." Infection and Immunity 81, no. 10 (July 22, 2013): 3684–92. http://dx.doi.org/10.1128/iai.00801-13.

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ABSTRACTInfection withHelicobacter pyloriis associated with development of ulcer disease and gastrointestinal adenocarcinoma. The infection leads to a large infiltration of immune cells and the formation of organized lymphoid follicles in the human gastric mucosa. Still, the immune system fails to eradicate the bacteria, and the substantial regulatory T cell (Treg) response elicited is probably a major factor permitting bacterial persistence. Dendritic cells (DCs) are professional antigen-presenting cells that can activate naive T cells, and maturation of DCs is crucial for the initiation of primary immune responses. The aim of this study was to investigate the presence and localization of mature human DCs inH. pylori-infected gastric mucosa. Gastric antral biopsy specimens were collected from patients withH. pylori-associated gastritis and healthy volunteers, and antrum tissue was collected from patients undergoing gastric resection. Immunohistochemistry and flow cytometry showed that DCs expressing the maturation marker dendritic cell lysosome-associated membrane glycoprotein (DC-LAMP; CD208) are enriched in theH. pylori-infected gastric mucosa and that these DCs are specifically localized within or close to lymphoid follicles. Gastric DC-LAMP-positive (DC-LAMP+) DCs express CD11c and high levels of HLA-DR but little CD80, CD83, and CD86. Furthermore, immunofluorescence analyses demonstrated that DC-LAMP+DCs are in the same location as FoxP3-positive putative Tregs in the follicles. In conclusion, we show that DC-LAMP+DCs with low costimulatory capacity accumulate in the lymphoid follicles in humanH. pylori-infected gastric tissue, and our results suggest that Treg-DC interactions may promote chronic infection by rendering gastric DCs tolerogenic.

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Akasaki, K., A. Michihara, Y. Fujiwara, K. Mibuka, and H. Tsuji. "Biosynthetic Transport of a Major Lysosome-Associated Membrane Glycoprotein 2, Lamp-2: A Significant Fraction of Newly Synthesized Lamp-2 Is Delivered to Lysosomes by Way of Early Endosomes." Journal of Biochemistry 120, no. 6 (December 1, 1996): 1088–94. http://dx.doi.org/10.1093/oxfordjournals.jbchem.a021526.

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Clemens, Daniel L., Bai-Yu Lee, and Marcus A. Horwitz. "Mycobacterium tuberculosis and Legionella pneumophila Phagosomes Exhibit Arrested Maturation despite Acquisition of Rab7." Infection and Immunity 68, no. 9 (September 1, 2000): 5154–66. http://dx.doi.org/10.1128/iai.68.9.5154-5166.2000.

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ABSTRACT Rab7 is a small GTPase that regulates vesicular traffic from early to late endosomal stages of the endocytic pathway. Phagosomes containing inert particles have also been shown to transiently acquire Rab7 as they mature. Disruption in the pathway prior to the acquisition of Rab7 has been suggested as playing a role in the altered maturation of Mycobacterium bovis BCG phagosomes. As a first step to determine whether disruption in the delivery or function of Rab7 could play a role in the altered maturation of Legionella pneumophila and M. tuberculosis phagosomes, we have examined the distribution of wild-type Rab7 and the GTPase-deficient, constitutively active mutant form of Rab7 in HeLa cells infected withL. pneumophila or M. tuberculosis. We have found that the majority of L. pneumophila and M. tuberculosis phagosomes acquire relatively abundant staining for Rab7 and for the constitutively active mutant Rab7 in HeLa cells that overexpress these proteins. Nevertheless, despite acquisition of wild-type or constitutively active Rab7, both the L. pneumophila and the M. tuberculosis phagosomes continue to exhibit altered maturation as manifested by a failure to acquire lysosome-associated membrane glycoprotein 1. These results demonstrate that L. pneumophila and M. tuberculosis phagosomes have receptors for Rab7 and that the altered maturation of these phagosomes is not due to a failure to acquire Rab7.

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Burkhardt, J. K., F. A. Wiebel, S. Hester, and Y. Argon. "The giant organelles in beige and Chediak-Higashi fibroblasts are derived from late endosomes and mature lysosomes." Journal of Experimental Medicine 178, no. 6 (December 1, 1993): 1845–56. http://dx.doi.org/10.1084/jem.178.6.1845.

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Chediak-Higashi Syndrome (CHS) is an autosomal recessive disease affecting secretory granules and lysosomes-like organelles. In CHS fibroblasts, acidic organelles are abnormally large and clustered in the perinuclear area. We have analyzed fibroblast cell lines from a CHS patient and from the murine model for CHS, the beige mouse, to determine which lysosome-like compartments are affected. Uptake of neutral red showed that in both beige and CHS cell lines, the acidic organelles were markedly clustered in the perinuclear region of the cells. Giant organelles (> 4 microns) were observed in a fraction of the cells, and these were more dramatic in the beige fibroblasts than in the CHS fibroblasts. The total dye uptake of both mutant cell lines was similar to their respective wild type fibroblasts, suggesting that the overall volume of acidic compartments is unaffected by the disorder. Histochemistry and immunofluorescence showed that the giant organelles in both beige and CHS fibroblasts were positive for cathepsin D, lysosome-associated membrane protein (LAMP) 1, LAMP 2, and a 120-kD lysosomal glycoprotein, all marker proteins for late endosomes and lysosomes. The giant organelles were also negative for transferrin receptor and mannose-6-phosphate receptor, and most of them were also negative for rab 7. This distribution of marker proteins shows that the giant organelles in both beige and CHS are derived from late compartments of the endocytic pathway. This conclusion was confirmed using endocytic tracers. BSA was transported to the giant organelles, but only after long incubation times, and only at 37 degrees C. alpha 2-Macroglobulin was taken up and degraded at similar rates by CHS or beige cells and their respective wild type control cells. Taken together, our results indicate that the mutation in CHS specifically affects late endosomes and lysosomes, with little or no effect on early endosomes. Although the mutation clearly causes mislocalization of these organelles, it appears to have little effect on their endocytic and degradative functions.

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Wildenberg, M. E., J. M. C. Welzen-Coppens, C. G. van Helden-Meeuwsen, H. Bootsma, A. Vissink, N. van Rooijen, J. P. van de Merwe, H. A. Drexhage, and M. A. Versnel. "Increased frequency of CD16+ monocytes and the presence of activated dendritic cells in salivary glands in primary Sjögren syndrome." Annals of the Rheumatic Diseases 68, no. 3 (April 8, 2008): 420–26. http://dx.doi.org/10.1136/ard.2008.087874.

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Objectives:In the salivary glands of patients with primary Sjögren Syndrome (pSjS) an accumulation of dendritic cells (DCs) is seen, which is thought to play a role in stimulating local inflammation. Aberrancies in subsets of monocytes, generally considered the blood precursors for DCs, may play a role in this accumulation of DCs. This study is aimed at determining the level of mature CD14lowCD16+ monocytes in pSjS and their contribution to the accumulation of DCs in pSjS.Methods:Levels of mature and immature monocytes in patients with pSjS (n = 19) and controls (n = 15) were analysed by flow cytometry. The reverse transmigration system was used for generation of DCs generated from monocyte subsets. The phenotype of DCs in pSjS salivary glands was analysed using immunohistochemistry. In vivo tracking of monocyte subsets was performed in a mouse model.Results:Increased levels of mature CD14lowCD16+ monocytes were found in patients with pSjS (mean (SD) 14.5 (5.5)% vs 11.4 (3.4)%). These cells showed normal expression of chemokine receptor and adhesion molecules. Mature monocytes partly developed into DC-lysosome-associated membrane glycoprotein (LAMP)+ (19.6 (7.5)%) and CD83+ (16 (9)%) DCs, markers also expressed by DCs in pSjS salivary glands. Monocyte tracking in the non-obese diabetic (NOD) mouse showed that the homologue population of mature mouse monocytes migrated to the salivary glands, and preferentially developed into CD11c+ DCs in vivo.Conclusions:Mature monocytes are increased in pSjS and patient and mouse data support a model where this mature monocyte subset migrates to the salivary glands and develops into DCs.

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Nabi, I. R., and E. Rodriguez-Boulan. "Increased LAMP-2 polylactosamine glycosylation is associated with its slower Golgi transit during establishment of a polarized MDCK epithelial monolayer." Molecular Biology of the Cell 4, no. 6 (June 1993): 627–35. http://dx.doi.org/10.1091/mbc.4.6.627.

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An endogenous Madin-Darby canine kidney (MDCK) lysosomal membrane glycoprotein that exhibits a basolateral targeting pathway to the lysosome is shown here to exhibit significant N-terminal amino acid sequence identity to lysosomal associated membrane proteins (LAMP-2) of other species. During establishment of the MDCK monolayer after only 1 d of culture, this canine LAMP-2 has a larger molecular size (110 kDa) than following formation of a confluent monolayer after 3 d of culture (100 kDa) due to the increased presence of N-linked polylactosamine oligosaccharide chains. Neither polylactosamine glycosylation of LAMP-2 in MDCK cells nor truncation of N-linked oligosaccharide chains of LAMP-2 in a ricin-resistant MDCK-RCAR cell line influenced the basolateral polarity of its targeting. However, the rate of basolateral delivery of LAMP-2 in MDCK cells plated for 3 d was significantly faster (t1/2 = 28 min) than in 1-d cells (t1/2 = 40 min); in MDCK-RCAR cells the rate of basolateral delivery at both 1 and 3 d of plating was similar (t1/2 = 40 min). The rate differential in MDCK cells occurred after arrival of LAMP-2 to the Golgi apparatus because the rate of acquisition of endoglycosidase H resistance was the same (t1/2 = 25 min) at both days of plating. The rate of transit of LAMP-2 through the Golgi apparatus to the basolateral domain was therefore far more rapid (approximately 4-fold) in 3 d compared with 1-d MDCK cultures. The increased polylactosamine glycosylation of MDCK LAMP-2 at early times of plating during the establishment of a confluent epithelial monolayer may thus be related to its longer residence time in the Golgi apparatus.

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Vandenabeele, Stéphane, Hubertus Hochrein, Nasim Mavaddat, Ken Winkel, and Ken Shortman. "Human thymus contains 2 distinct dendritic cell populations." Blood 97, no. 6 (March 15, 2001): 1733–41. http://dx.doi.org/10.1182/blood.v97.6.1733.

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In this study, 2 distinct populations of mature dendritic cells (DCs) were identified in the human thymus. The major population is CD11b−, CD11c+, and CD45ROlowand does not express myeloid-related markers. It displays all the characteristics of mature DCs with a typical dendritic morphology, high surface levels of HLA-DR, CD40, CD83, and CD86, and expression of DC–lysosome-associated membrane glycoprotein messenger RNA (mRNA). In addition, CD11b− thymic DCs do not express macrophage inflammatory protein-1α (MIP-1α) mRNA, but express thymus-expressed chemokine (TECK) mRNA and are able to secrete bioactive interleukin 12 (IL-12) upon stimulation. In contrast, the minor and variable thymic DC population is CD11b+, CD11chigh, and CD45ROhigh and comprises CD83+CD14− mature and CD83−CD14+ immature DCs. It expresses macrophage-colony stimulating factor receptor, MIP-1α mRNA and high amounts of decysin mRNA after CD40 activation, but does not express TECK and is a weak bioactive IL-12 producer. Also identified were the IL-3Rαhigh plasmacytoid cells, which are present in the thymic cortex and medulla. Upon culture with IL-3, granulocyte/macrophage–colony stimulating factor, and CD40 ligand, the plasmacytoid cells can adopt a phenotype resembling that of freshly isolated CD11b− thymic DCs. However, these plasmacytoid-derived DCs fail to secrete bioactive IL-12; therefore, conclusions cannot be made about a direct relation between thymic plasmacytoid cells and CD11b− DCs. Whereas CD11b+ thymic DCs appear to be related to tonsillar germinal-center DCs, the major CD11b− IL-12–secreting human thymus DC population has similarities to mouse CD11b− CD8+ DCs.

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Smith, Gina A., Gareth W. Fearnley, Darren C. Tomlinson, Michael A. Harrison, and Sreenivasan Ponnambalam. "The cellular response to vascular endothelial growth factors requires co-ordinated signal transduction, trafficking and proteolysis." Bioscience Reports 35, no. 5 (September 29, 2015). http://dx.doi.org/10.1042/bsr20150171.

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VEGFs (vascular endothelial growth factors) are a family of conserved disulfide-linked soluble secretory glycoproteins found in higher eukaryotes. VEGFs mediate a wide range of responses in different tissues including metabolic homoeostasis, cell proliferation, migration and tubulogenesis. Such responses are initiated by VEGF binding to soluble and membrane-bound VEGFRs (VEGF receptor tyrosine kinases) and co-receptors. VEGF and receptor splice isoform diversity further enhances complexity of membrane protein assembly and function in signal transduction pathways that control multiple cellular responses. Different signal transduction pathways are simultaneously activated by VEGFR–VEGF complexes with membrane trafficking along the endosome–lysosome network further modulating signal output from multiple enzymatic events associated with such pathways. Balancing VEGFR–VEGF signal transduction with trafficking and proteolysis is essential in controlling the intensity and duration of different intracellular signalling events. Dysfunction in VEGF-regulated signal transduction is important in chronic disease states including cancer, atherosclerosis and blindness. This family of growth factors and receptors is an important model system for understanding human disease pathology and developing new therapeutics for treating such ailments.

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Li, Qian, Daming Chen, Qiwang Xiang, and John Nicholas. "Insulin-Like Growth Factor 2 Receptor Expression Is Promoted by Human Herpesvirus 8-Encoded Interleukin-6 and Contributes to Viral Latency and Productive Replication." Journal of Virology 93, no. 5 (December 12, 2018). http://dx.doi.org/10.1128/jvi.02026-18.

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ABSTRACTHuman herpesvirus 8 (HHV-8) viral interleukin-6 (vIL-6) localizes largely to the endoplasmic reticulum (ER) and here associates functionally with both the gp130 signal transducer and the novel ER membrane protein vitamin K epoxide reductase complex subunit 1 variant-2 (VKORC1v2). The latter interaction contributes to the viability of latently infected primary effusion lymphoma (PEL) cells and to HHV-8 productive replication, in part via promotion of ER-associated degradation (ERAD) of nascent pro-cathepsin D (pCatD) and consequent suppression of lysosome-localized proapoptotic mature CatD. Here we report that VKORC1v2 associates with insulin-like growth factor 2 receptor (IGF2R), also known as cation-independent mannose-6-phosphate receptor, which is involved in trafficking of mannose-6-phosphate-conjugated glycoproteins to lysosomes. VKORC1v2 effected reduced IGF2R expression in a manner dependent on VKORC1v2-IGF2R interaction, while vIL-6, which could inhibit VKORC1v2-IGF2R interaction, effected increased expression of IGF2R. These effects were independent of changes in IGF2R mRNA levels, indicating likely posttranslational mechanisms. In kinetic analyses involving labeling of either newly synthesized or preexisting IGF2R, vIL-6 promoted accumulation of the former while having no detectable effect on the latter. Furthermore, vIL-6 led to decreased K48-linked ubiquitination of IGF2R and suppression of ERAD proteins effected increased IGF2R expression and loss of IGF2R regulation by vIL-6. Depletion-based experiments identified IGF2R as a promoter of PEL cell viability and virus yields from lytically reactivated cultures. Our findings identify ER-transiting nascent IGF2R as an interaction partner of VKORC1v2 and target of vIL-6 regulation and IGF2R as a positive contributor to HHV-8 biology, thereby extending understanding of the mechanisms of VKORC1v2-associated vIL-6 function.IMPORTANCEHHV-8 vIL-6 promotes productive replication in the context of reactivated lytic replication in primary effusion lymphoma (PEL) and endothelial cells and sustains latently infected PEL cell viability. Viral IL-6 is also considered to contribute significantly to HHV-8-associated pathogenesis, since vIL-6 can promote cell proliferation, cell survival, and angiogenesis that are characteristic of HHV-8-associated Kaposi’s sarcoma, PEL and multicentric Castleman’s disease (MCD), in addition to proinflammatory activities observed in MCD-like “Kaposi’s sarcoma-associated herpesvirus-induced cytokine syndrome.” We show in the present study that vIL-6 can promote productive replication and latent PEL cell viability through upregulation of the mannose-6-phosphate- and peptide hormone-interacting receptor IGF2R, which is a positive factor in HHV-8 biology via these activities. VKORC1v2-enhanced ER-associated degradation of IGF2R and vIL-6 promotion of IGF2R expression through prevention of its interaction with VKORC1v2 and consequent rescue from degradation represent newly recognized activities of VKOCR1v2 and vIL-6.

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Pan, Peng, Ting Chen, Yanmin Zhang, Zhengyu Qi, Jie Qin, Guanghui Cui, and Xin Guo. "LIN28A inhibits lysosome‑associated membrane glycoprotein 1 protein expression in embryonic stem and bladder cancer cells." Molecular Medicine Reports, May 3, 2018. http://dx.doi.org/10.3892/mmr.2018.8965.

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Nawaratna, Sujeevi S. K., Geoffrey N. Gobert, Charlene Willis, Jason Mulvenna, Andreas Hofmann, Donald P. McManus, and Malcolm K. Jones. "Lysosome-associated membrane glycoprotein (LAMP) – preliminary study on a hidden antigen target for vaccination against schistosomiasis." Scientific Reports 5, no. 1 (October 16, 2015). http://dx.doi.org/10.1038/srep15069.

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Journal articles on the topic 'Lysosome-associated membrane glycoproteins'

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