Journal
GENES & DEVELOPMENT
Volume 26, Issue 8, Pages 816-829Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.184481.111
Keywords
endosome; photoreceptor degeneration; retinal pigment epithelial cell; Semaphorin 4A
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Funding
- JSPS
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Ministry of Health, Labour, and Welfare
- National Institute of Biomedical Innovation
- Funding Program for Next-Generation World-Leading Researchers (NEXT Program)
- Special Coordination Funds for Promoting Science and Technology
- Grants-in-Aid for Scientific Research [24590285, 23390069] Funding Source: KAKEN
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Photoreceptor cell death is the hallmark of a group of human inherited retinal degeneration. Although the causative genetic mutations are often known, the mechanisms leading to photoreceptor degeneration remain poorly defined. Here, we show that Semaphorin 4A (Sema4A), a member of axonal guidance molecule semaphorin, plays a role in Rab11/FIP2-mediated endosomal sorting in retinal pigment epithelial cells to support photoreceptor function. In response to oxidative stress, Sema4A switches the endosomal sorting of the lysosomal precursor protein prosaposin from the lysosome to the exosomal release, which prevents light-induced photoreceptor apoptosis. In the absence of oxidative stress, Sema4A sorts retinoid-binding proteins with retinoids between the cell surface and endoplasmic reticulum, by which 11-cis-retinal, a chromophore for phototransduction, is regenerated and transported back to photoreceptors. Owing to defects in these processes, Sema4A-deficient mice exhibit marked photoreceptor degeneration. Our findings therefore indicate that Sema4A regulates two distinct endosomal-sorting pathways that are critical for photoreceptor survival and phototransduction during the transition between daylight and darkness.
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