Cul3‐Klhl18 ubiquitin ligase modulates rod transducin translocation during light‐dark adaptation

Adaptation is a general feature of sensory systems. In rod photoreceptors, light‐dependent transducin translocation and Ca 2+ homeostasis are involved in light/dark adaptation and prevention of cell damage by light. However, the underlying regulatory mechanisms remain unclear. Here, we identify mammalian Cul3‐Klhl18 ubiquitin ligase as a transducin translocation modulator during light/dark adaptation. Under dark conditions, Klhl18 −/− mice exhibited decreased rod light responses and subcellular localization of the transducin α‐subunit (Tα), similar to that observed in light‐adapted Klhl18 +/+ mice. Cul3‐Klhl18 promoted ubiquitination and degradation of Unc119, a rod Tα‐interacting protein. Unc119 overexpression phenocopied Tα mislocalization observed in Klhl18 −/− mice. Klhl18 weakly recognized casein kinase‐2‐phosphorylated Unc119 protein, which is dephosphorylated by Ca 2+ ‐dependent phosphatase calcineurin. Calcineurin inhibition increased Unc119 expression and Tα mislocalization in rods. These results suggest that Cul3‐Klhl18 modulates rod Tα translocation during light/dark adaptation through Unc119 ubiquitination, which is affected by phosphorylation. Notably, inactivation of the Cul3‐Klhl18 ligase and calcineurin inhibitors FK 506 and cyclosporine A that are known immunosuppressant drugs repressed light‐induced photoreceptor damage, suggesting potential therapeutic targets.