Degradation of STK16 via KCTD17 with Ubiquitin–Proteasome System in Relation to Sleep–Wake Cycle

Abstract

Serine/threonine-protein kinase 16 (STK16) is a novel member of the Numb-associated family of protein kinases with an atypical kinase domain. In this study, we aimed to investigate the involvement of STK16 in sleep–wake mechanisms. We confirmed the expression of Stk16 in the murine hypothalamus, the sleep–wake center, and found considerable changes in STK16 protein levels in the anterior hypothalamus during the light–dark cycle. We found that the coexistence of the potassium channel tetramerization domain containing 17 (KCTD17), an STK16 interactor, caused STK16 degradation. In contrast, the proteasome inhibitor MG132 inhibited the degradation of STK16. In addition, polyubiquitinated STK16 was observed, suggesting that KCTD17 acts as an adapter for E3 ligase to recognize STK16 as a substrate, leading to STK16 degradation via the ubiquitin–proteasome system. The vast changes in STK16 in the anterior hypothalamus, a mammalian sleep center, as well as the reported sleep abnormalities in the ubiquitin B knockout mice and the Drosophila with the inhibition of the KCTD17 homolog or its E3 ligase cullin-3, suggest that STK16 plays a major role in sleep–wake regulation.