title: Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival.
abstract: 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.
authors.affiliation: World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan. toyofuku@imed3.med.osaka-u.ac.jp
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Toyofuku
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nojima
authors.forename: Takako
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Hyota
authors.initials: H
authors.lastname: Takamatsu
authors.forename: Tohru
authors.initials: T
authors.lastname: Tsujimura
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Uemura
authors.forename: Junko
authors.initials: J
authors.lastname: Matsuda
authors.forename: Takaharu
authors.initials: T
authors.lastname: Seki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002470:Cell Survival; D011992:Endosomes / Q000378:metabolism*; D005136:Eye Proteins / Q000378:metabolism; D008027:Light; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020419:Photoreceptor Cells, Vertebrate / Q000166:cytology* / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D049231:Saposins / Q000378:metabolism; D039961:Semaphorins / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D018797:Cell Cycle Proteins; D005136:Eye Proteins; D026901:Membrane Transport Proteins; D049231:Saposins; D039961:Semaphorins; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C501288:Optn protein, mouse; C483344:Psap protein, mouse; C534721:Sema4A protein, mouse