AbstractThe light detecting protein, Rhodopsin, requires retinoid chromophores for their function. In vertebrates, retinoids also serve as signaling molecules, but whether these molecules similarly regulate gene expression inDrosophilaremains unclear. Here, we report the identification of a retinoid-inducible gene inDrosophila,highroad, which is required for photoreceptors to clear folding-defective mutant Rhodopsin-1 proteins. Specifically, we identifiedhighroadthrough an in vivo RNAi based genetic interaction screen with one such folding defective Rhodopsin-1 mutant,ninaEG69D. CRISPR-Cas9-mediated deletion ofhighroadresults in the stabilization of folding-defective mutant Rhodopsin-1 proteins, and acceleration of the age-related retinal degeneration phenotype ofninaEG69Dmutants. Elevatedhighroadtranscript levels are detectedninaEG69Dflies, and interestingly, deprivation of retinoids in the fly diet blocks this effect. Consistently, mutations in the retinoid transportersanta mariaimpairs the induction ofhighroadinninaEG69Dflies. In cultured S2 cells,highroadexpression is induced by retinoic acid treatment. These results indicate that cellular quality control mechanism against misfolded Rhodopsin-1 involves regulation of gene expression by retinoids.