Suppression of gluconeogenic gene transcription by SIK1-induced ubiquitination and degradation of CRTC1.

摘要: CRTCs are a group of three transcriptional coactivators required for CREB-dependent transcription. CREB and critically involved in the regulation various biological processes such as cell proliferation, metabolism, learning memory. However, whether CRTC1 efficiently induces gluconeogenic gene expression how is regulated by upstream kinase SIK1 remain to be understood. In this work, we demonstrated SIK1-induced phosphorylation, ubiquitination degradation context gluconeogenesis. protein was destabilized but not SIK2 or SIK3. This effect likely mediated phosphorylation at S155, S167, S188 S346 residues followed K48-linked polyubiquitination proteasomal degradation. Expression genes that coding phosphoenolpyruvate carboxykinase stimulated CRTC1, suppressed SIK1. Depletion also blocked forskolin-induced expression, knockdown pharmaceutical inhibition had opposite effect. Finally, RFWD2 ubiquitin ligase site equivalent K628 CRTC2. Taken together, our work reveals regulatory circuit which suppresses transcription inducing CRTC1. Our findings have implications development new antihyperglycemic agents.