Preserving the UFMylation-cilium axis mitigates blue light-induced retinal degeneration.

Abstract

Blue light damage (BLD) is a complex process implicated in a variety of ocular diseases, including age-related macular degeneration and dry eye diseases. However, the molecular mechanisms underlying the BLD process remain largely unknown. In this study, using a mouse model, we identify photoreceptor cilium disruption as a key event in BLD and show that the UFMylation of kinesin family member 11 (KIF11) is decreased under BLD conditions. We further reveal that ubiquitin-fold modifier 1-specific ligase 1 (UFL1), the sole ligase for UFMylation, localizes to the basal body and is required for maintaining photoreceptor cilia. Strikingly, exposure to blue light disrupts the basal body localization of UFL1, leading to ciliary defects and subsequent photoreceptor dysfunction. Ufl1 knockout mice exhibit similar ciliary donlefects and retinal impairments. Importantly, intravitreal injection of agents that enhance UFMylation or ciliogenesis can mitigate the pathological changes induced by blue light exposure. These findings establish that UFL1-mediated ciliary integrity contributes to retinal deficits associated with BLD and demonstrate that targeting the UFMylation-cilium axis represents a promising therapeutic strategy for BLD-associated retinal diseases.