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 CA²⁺ 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 CA²⁺ -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 FK506 and cyclosporine A that are known immunosuppressant drugs repressed light-induced photoreceptor damage, suggesting potential therapeutic targets.