Regulation of phagolysosomal digestion by caveolin-1 of the retinal pigment epithelium is essential for vision

Saumil Sethna, Tess Chamakkala, Xiaowu Gu, Timothy C. Thompson, Guangwen Cao, Michael H. Elliott, Silvia C. Finnemann

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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, RPECAV1-/- 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. RPECAV1-/- 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 lysosomalpHand 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.

Original languageEnglish (US)
Pages (from-to)6494-6506
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number12
DOIs
StatePublished - Mar 18 2016
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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