Drosophila fabpis a retinoid-inducible gene required for Rhodopsin-1 homeostasis and photoreceptor survival

Abstract

AbstractRetinoids act as chromophore co-factors for light-detecting rhodopsin proteins. In vertebrates, retinoids also actively regulate gene expression. Whether retinoids regulate gene expression inDrosophilafor a specific biological function remains unclear. Here, we report thatDrosophila fatty acid binding protein(fabp) is a retinoid-inducible gene required for Rhodopsin-1 (Rh1) protein homeostasis and photoreceptor survival. Specifically, we performed a photoreceptor-specific gene expression profiling study in flies bearing a misfolding-prone Rhodopsin-1 (Rh1) mutant,ninaEG69D, which serves as aDrosophilamodel for Retinitis Pigmentosa.ninaEG69Dphotoreceptors showed increased expression of genes that control Rh1 protein levels, along with a poorly characterized gene,fabp. We found that in vivofabpexpression was reduced when the retinoids were deprived through independent methods. Conversely,fabpmRNA was induced when we challenged culturedDrosophilacells with retinoic acid. In flies reared under light, loss offabpcaused an accumulation of Rh1 proteins in cytoplasmic vesicles.fabpmutants exhibited light-dependent retinal degeneration, a phenotype also found in other mutants that block light-activated Rh1 degradation. These observations indicate that a retinoid-inducible gene expression program regulatesfabpthat is required for Rh1 proteostasis and photoreceptor survival.Author SummaryRhodopsins are light-detecting proteins that use retinoids as chromophore co-factors. In vertebrates, retinoids also actively regulate gene expression. Whether retinoids regulate Rhodopsin function aside from its role as a chromophore remains unclear. Here, we report thatDrosophila fatty acid binding protein(fabp) is a retinoid-inducible gene required for Rhodopsin-1 (Rh1) protein homeostasis and photoreceptor survival. Specifically, we found thatfabpis among the genes induced by a misfolding-prone Rhodopsin-1 (Rh1) mutant,ninaEG69D, which serves as aDrosophilamodel for Retinitis Pigmentosa. We further found thatfabpinduction inninaEG69Dphotoreceptors required retinoids.fabpwas required in photoreceptors to help degrade light-activated Rh1. In the absence offabp, Rh1 accumulated in cytoplasmic vesicles in a light-dependent manner, and exhibited light-dependent retinal degeneration. These observations indicate that a retinoid-inducible gene expression program regulatesfabpthat is required for Rh1 proteostasis and photoreceptor survival.