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

Abstract

Retinoids act as chromophore co-factors for light-detecting rhodopsin proteins. In vertebrates, retinoids also actively regulate gene expression. Whether retinoids regulate gene expression in Drosophila for a specific biological function remains unclear. Here, we report that Drosophila 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 a Drosophila model for Retinitis Pigmentosa. ninaEG69D photoreceptors showed increased expression of genes that control Rh1 protein levels, along with a poorly characterized gene, fabp. We found that in vivo fabp expression was reduced when the retinoids were deprived through independent methods. Conversely, fabp mRNA was induced when we challenged cultured Drosophila cells with retinoic acid. In flies reared under light, loss of fabp caused an accumulation of Rh1 proteins in cytoplasmic vesicles. fabp mutants 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 regulates fabp that 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 that Drosophila fatty acid binding protein (fabp) is a retinoid-inducible gene required for Rhodopsin-1 (Rh1) protein homeostasis and photoreceptor survival. Specifically, we found that fabp is among the genes induced by a misfolding-prone Rhodopsin-1 (Rh1) mutant, ninaEG69D, which serves as a Drosophila model for Retinitis Pigmentosa. We further found that fabp induction in ninaEG69D photoreceptors required retinoids. fabp was required in photoreceptors to help degrade light-activated Rh1. In the absence of fabp, 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 regulates fabp that is required for Rh1 proteostasis and photoreceptor survival.