SUMMARY Non-canonical autophagy or LC3-associated phagocytosis (LAP) is essential for the maintenance and functioning of the retinal pigment epithelium (RPE) and photoreceptors. Although molecular mechanisms still remain elusive, deficits in LAP have been found to be associated with age-related retinal pathology in both mice and humans. In this study, we found that calcium and integrin-binding protein 2 (CIB2) regulates LAP in the RPE. Mice lacking CIB2, both globally and specifically within RPE, have an impaired ability to process the engulfed photoreceptor outer segments due to reduced lysosomal capacity, which leads to marked accumulation of improperly digested remnants, lipid droplets, fused phago-melanosomes in RPE, and impaired visual function. In aged mice, we also found marked accumulation of drusen markers APOE, C3, and Aβ, along with esterified cholesterol. Intriguingly, we were able to transiently rescue the photoreceptor function in Cib2 mutant mice by exogenous retinoid delivery. Our study links LAP and phagocytic clearance with CIB2, and their relevance to the sense of sight.

Loss of CIB2 causes non-canonical autophagy deficits and visual impairment