| First Author | Chaya T | Year | 2019 |
| Journal | EMBO J | Volume | 38 |
| Issue | 23 | Pages | e101409 |
| PubMed ID | 31696965 | Mgi Jnum | J:282598 |
| Mgi Id | MGI:6383261 | Doi | 10.15252/embj.2018101409 |
| Citation | Chaya T, et al. (2019) Cul3-Klhl18 ubiquitin ligase modulates rod transducin translocation during light-dark adaptation. EMBO J 38(23):e101409 |
| abstractText | 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 alpha-subunit (Talpha), similar to that observed in light-adapted Klhl18(+/+) mice. Cul3-Klhl18 promoted ubiquitination and degradation of Unc119, a rod Talpha-interacting protein. Unc119 overexpression phenocopied Talpha 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 Talpha mislocalization in rods. These results suggest that Cul3-Klhl18 modulates rod Talpha 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. |
