Caveolin targeting to late endosome/lysosomal membranes is induced by perturbations of lysosomal pH and cholesterol content

Mundy, Dorothy I.; Li, Wei Ping; Luby-Phelps, Katherine; Anderson, Richard G. W.

doi:10.1091/mbc.e11-07-0598

Cited by 56 publications

(75 citation statements)

References 90 publications

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“…Notably, non-canonical autophagy shares components with clearance phagocytosis pathways (53,54). Recent studies have demonstrated the importance of caveolin-1 in multifunctional endosomal and lysosomal compartments (21,55). Our results extend these observations, showing that phagosomes are regulated by caveolin-1 as well.…”

Section: Discussionsupporting

confidence: 86%

Regulation of Phagolysosomal Digestion by Caveolin-1 of the Retinal Pigment Epithelium Is Essential for Vision

Sethna

Chamakkala

et al. 2016

Journal of Biological Chemistry

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Caveolin-1 associates with the endo/lysosomal machinery of cells in culture, suggesting that it functions at these organelles independently of its contribution to cell surface caveolae. Here we explored mice lacking caveolin-1 specifically in the retinal pigment epithelium (RPE Support of the neural retina generally and of adjacent photoreceptor neurons specifically by the retinal pigment epithelium (RPE) 5 is essential for vision (1). A major function of the RPE is its contribution to photoreceptor outer segment renewal, a continuous and life-long rejuvenation process that involves the formation of new membrane disks at the proximal end of the outer segment and diurnal shedding of distal spent outer segment tips (2). Outer segment renewal is critical for photoreceptor function and survival, and any abnormality is thought to impair vision. RPE cells participate in outer segment renewal by clearing shed photoreceptor outer segment fragments (POS) by receptor-mediated phagocytosis (3).Mechanistically, RPE phagocytosis belongs to a family of conserved non-inflammatory clearance phagocytosis pathways that other cell types use to remove apoptotic cells and debris. These pathways have in common that their failure to efficiently clear debris contributes to human disease. However, unlike other forms of phagocytosis, RPE clearance of POS occurs in a strict diurnal rhythm that is regulated by light and circadian mechanisms (4). This is a unique advantage for RPE phagocytosis studies because all steps of the synchronized phagocytic process may be quantified precisely in situ in the intact, undisturbed retinas of experimental animals. Content in the RPE of engulfed rod POS phagosomes peaks shortly after light onset and declines characteristically within several hours as RPE cells complete digestion of their phagocytic load before the next burst of intake (5).Like other phagocytic pathways, ingested phagosomes in the RPE fuse with lysosomal vesicles to form phagolysosomes. In POS phagolysosomes, degradation of opsin, which constitutes ϳ85% of POS protein, requires the aspartic protease cathepsin D and phagosomal acidification (6, 7). Because RPE cells are post-mitotic in the mammalian eye and ingest numerous POS daily, prompt and complete POS engulfment is essential to prevent gradual buildup of undigested debris in the RPE (8). Inefficient RPE lysosomal function causes accumulation of debris in human and experimental animal RPE that can be toxic and

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Section: Discussionsupporting

confidence: 86%

Regulation of Phagolysosomal Digestion by Caveolin-1 of the Retinal Pigment Epithelium Is Essential for Vision

Sethna

Chamakkala

et al. 2016

Journal of Biological Chemistry

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“…6 At present, there are two lines of evidence demonstrating that CAV1 is also involved in lipid rafts: (i) CAV1 plays an important role in the regulation of cholesterol homeostasis in various membrane structures, 4,6 and (ii) distribution of CAV1 in cellular organelles such as mitochondria, endoplasmic reticulum, and the late endosome/lysosome, has also been well reported. [7][8][9] In this study, we provide convincing evidence demonstrating that the function of CAV1 in autophagy is most probably lipid raft-dependent but caveolae-independent. First, depletion of another critical caveolae regulator PTRF did not affect autophagy (Fig.…”

Section: Discussionsupporting

confidence: 63%

“…4,5 In addition, compared to the limited distribution on the plasma membrane of caveolae, 6 CAV1 has a more extensive membrane distribution including mitochondria, endoplasmic reticulum, as well as the late endosome/lysosome, indicating the existence of caveolae-independent function of CAV1 in the intracellular membrane system. [7][8][9] There is emerging evidence demonstrating the tumor-suppression functions of CAV1 in several types of cancer, especially in breast cancer. 10 For instance, expression of oncogenes (such as ABL1/v-abl and HRAS/H-ras) leads to a significant decrease in CAV1 protein and mRNA levels.…”

Section: Introductionmentioning

confidence: 99%

Critical role of CAV1/caveolin-1 in cell stress responses in human breast cancer cells via modulation of lysosomal function and autophagy

et al. 2015

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CAV1 (caveolin 1, caveolae protein, 22kDa) is well known as a principal scaffolding protein of caveolae, a specialized plasma membrane structure. Relatively, the caveolae-independent function of CAV1 is less studied. Autophagy is a process known to involve various membrane structures, including autophagosomes, lysosomes, and autolysosomes for degradation of intracellular proteins and organelles. Currently, the function of CAV1 in autophagy remains largely elusive. In this study, we demonstrate for the first time that CAV1 deficiency promotes both basal and inducible autophagy. Interestingly, the promoting effect was found mainly in the late stage of autophagy via enhancing lysosomal function and autophagosome-lysosome fusion. Notably, the regulatory function of CAV1 in lysosome and autophagy was found to be caveolae-independent, and acts through lipid rafts. Furthermore, the elevated autophagy level induced by CAV1 deficiency serves as a cell survival mechanism under starvation. Importantly, downregulation of CAV1 and enhanced autophagy level were observed in human breast cancer cells and tissues. Taken together, our data reveal a novel function of CAV1 and lipid rafts in breast cancer development via modulation of lysosomal function and autophagy.

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“…Like clathrin-mediated endocytosis, caveolar internalization is another well-characterized dynamindependent endocytic pathway, which is initiated by invagination of smooth patches of plasma membrane where cholesterol and sphingolipids are abundant (31). Numerous inhibitors have been reported to effectively block caveolar maturation, including genistein (31), filipin (32), nystatin (33), and M␤CD (34). Treatment of cells with genistein resulted in a significant increase of cell surface MHC-I in infected cells in a dose-dependent manner (Fig.…”

Section: Resultsmentioning

confidence: 99%

Major Histocompatibility Complex Class I Downregulation Induced by Equine Herpesvirus Type 1 pUL56 Is through Dynamin-Dependent Endocytosis

Huang

Lehmann

Said

et al. 2014

J Virol

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Here, we report that cell surface MHC-I in EHV-1-infected cells is internalized and degraded in the lysosomal compartment in a pUL56-dependent fashion. pUL56-induced MHC-I endocytosis required dynamin and tyrosine kinase but was independent of clathrin and caveolin-1, the main constituents of the clathrin-and raft/caveola-mediated endocytosis pathways, respectively. Downregulation of cell surface MHC-I was significantly inhibited by the ubiquitin-activating enzyme E1 inhibitor PYR41, indicating that ubiquitination is essential for the process. Finally, we show that downregulation is not specific for MHC-I and that other molecules, including CD46 and CD63, are also removed from the cell surface in a pUL56-dependent fashion. IMPORTANCEWe show that alphaherpesvirus induces MHC-I downregulation through endocytosis, which is mediated by pUL56. The dynamin-dependent endocytic pathway is responsible for MHC-I internalization in infected cells. Furthermore, we discovered that this endocytic process can be disrupted by the inhibiting ubiquitin-activating E1 enzyme, which is indispensable for ubiquitination. Finally, pUL56 action extends to a number of cell surface molecules that are significant for host immunity. Therefore, the protein may exert a more general immunomodulatory effect.

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Caveolin targeting to late endosome/lysosomal membranes is induced by perturbations of lysosomal pH and cholesterol content

Cited by 56 publications

References 90 publications

Regulation of Phagolysosomal Digestion by Caveolin-1 of the Retinal Pigment Epithelium Is Essential for Vision

Regulation of Phagolysosomal Digestion by Caveolin-1 of the Retinal Pigment Epithelium Is Essential for Vision

Critical role of CAV1/caveolin-1 in cell stress responses in human breast cancer cells via modulation of lysosomal function and autophagy

Major Histocompatibility Complex Class I Downregulation Induced by Equine Herpesvirus Type 1 pUL56 Is through Dynamin-Dependent Endocytosis

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