title: Regulation of Phagolysosomal Digestion by Caveolin-1 of the Retinal Pigment Epithelium Is Essential for Vision.
abstract: 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). The RPE supports neighboring photoreceptors via diurnal phagocytosis of spent photoreceptor outer segment fragments. Like mice lacking caveolin-1 globally, (RPE)CAV1(-/-) mice developed a normal RPE and neural retina but showed reduced rod photoreceptor light responses, indicating that lack of caveolin-1 affects photoreceptor function in a non-cell-autonomous manner. (RPE)CAV1(-/-) RPE in situ showed normal particle engulfment but delayed phagosome clearance and reversed diurnal profiles of levels and activities of lysosomal enzymes. Therefore, eliminating caveolin-1 specifically impairs phagolysosomal degradation by the RPE in vivo. Endogenous caveolin-1 was recruited to maturing phagolysosomes in RPE cells in culture. Consistent with these in vivo data, a moderate increase (to ∼ 2.5-fold) or decrease (by half) of caveolin-1 protein levels in RPE cells in culture was sufficient to accelerate or impair phagolysosomal digestion, respectively. A mutant form of caveolin-1 that fails to reach the cell surface augmented degradation like wild-type caveolin-1. Acidic lysosomal pH and increased protease activity are essential for digestion. We show that halving caveolin-1 protein levels significantly alkalinized lysosomal pH and decreased lysosomal enzyme activities. Taken together, our results reveal a novel role for intracellular caveolin-1 in modulating phagolysosomal function. Moreover, they show, for the first time, that organellar caveolin-1 significantly affects tissue functionality in vivo.
authors.affiliation: From the Department of Biological Sciences, Center for Cancer Genetic Diseases and Gene Regulation, Fordham University, Bronx, New York 10458.
authors.forename: Saumil
authors.initials: S
authors.lastname: Sethna
authors.affiliation: From the Department of Biological Sciences, Center for Cancer Genetic Diseases and Gene Regulation, Fordham University, Bronx, New York 10458.
authors.forename: Tess
authors.initials: T
authors.lastname: Chamakkala
authors.affiliation: the Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, and.
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Gu
authors.affiliation: the Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Thompson
authors.affiliation: the Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Guangwen
authors.initials: G
authors.lastname: Cao
authors.affiliation: the Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, and michael-elliott@ouhsc.edu.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Elliott
authors.affiliation: From the Department of Biological Sciences, Center for Cancer Genetic Diseases and Gene Regulation, Fordham University, Bronx, New York 10458, finnemann@fordham.edu.
authors.forename: Silvia C
authors.initials: SC
authors.lastname: Finnemann
mesh_terms: D000818:Animals; D002402:Cathepsin D / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism*; D002460:Cell Line; D002940:Circadian Rhythm; D008247:Lysosomes / Q000201:enzymology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D010588:Phagosomes / Q000378:metabolism; D021381:Protein Transport; D059748:Proteolysis; D051381:Rats; D011990:Receptors, Transferrin / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism; D034421:Sus scrofa; D014785:Vision, Ocular
chemical_list: D051242:Caveolin 1; D011990:Receptors, Transferrin; D002402:Cathepsin D
keywords: caveolin; clearance; digestion; lysosomal acidification; lysosome; phagocytosis; retina; retinal pigment epithelium
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