Tzou, F.Y., Chuang, P.H., Hsu, C.H., Wu, C.H., Hsiao, Y., Liu, C.C., Yu, Y.L., Yeh, Y.H., Lin, C.W., Chan, C.C., Huang, S.Y. (2025). Dihydroceramide desaturase modulates autolysosome maturation and ameliorates CRB1 retinopathy.  Biochim Biophys Acta Mol Basis Dis 1871(5): 167736.

FBrf0262072

Research paper

Variants in the CRB1 gene cause retinal degeneration and subsequent vision impairment in patients of retinitis pigmentosa (RP). No treatments are currently available to cure or impede the progression of CRB1-associated retinopathy. Previous studies have revealed alterations in the endolysosomal systems and autophagy in the absence of CRB1, but their roles in the pathogenesis of CRB1 retinopathy are unclear. Here, we examined the disease mechanism of CRB1 retinopathy using loss-of-function mutants of crumbs (crb), the Drosophila homolog of CRB1. We found that the loss of crb results in overactivation of autophagy in the eye. We also discovered that dihydroceramide desaturase encoded by infertile crescent (ifc), was up-regulated in crb mutants. Overexpression of ifc inhibited autolysosomes and alleviated Atg1-induced autophagic cell death. Mechanistically, ifc enhanced the binding of Rac1 to Atg8 and increased the autophagosomal localization of active Rac1, thus inhibiting autophagy. Importantly, autophagy inhibitions achieved through ifc overexpression, chloroquine treatment, or Beclin-1 RNAi all ameliorated the neurodegeneration of crb mutant eyes. Together, these findings highlight the mechanism of dihydroceramide desaturase in modulating autolysosome functions in crb mutants, providing new insights for developing treatments against CRB1 retinopathy.