A CK2-RNF4 interplay coordinates non-canonical SUMOylation and degradation of nuclear receptor FXR

• 来源期刊: 分子细胞生物学报（英文版）
• 年，卷（期）: 2017,（3）
• 页码范围: 195-208
• 页数: 14页
• 语种: 英文
• DOI: 10.1093/jmcb/mjx009

摘要

Farnesoid X receptor (FXR) is a ligand-activated nuclear receptor that plays a central role in regulating genes involved in bile acid homeostasis,and fat and glucose metabolism.Here,we demonstrate a post-translational interplay between FXR phosphorylation,SUMOylation,and ubiquitination that directs the receptor into an activation-degradation pathway in hepatocytes.We identify a non-canonical SUMOylation motif termed pSuM that conjugates SUMO2 at Lys-325 of FXR under the direct control of casein kinase 2 (CK2),which provides the required negative charge for Ubc9 and PIAS1 to perform SUMOylation,by phosphorylating Ser-327.Lys-325 SUMOylation is indispensable to the promotion of efficient ligand activation and transcriptional coactivation of FXR.Constitutive pSuM activation using a phospho-mimic Ser-327 mutant or catalytic CK2 expression strongly induces SUMO2 conjugation,which directs FXR ubiquitination and proteasome-dependent degradation.We also determine that such SUMOylation-dependent ubiquitination of FXR is mediated by the E3 ubiquitin ligase RNF4,which is required to achieve maximal induction of FXR and optimal up-or downregulation of responsive genes involved in bile acid homeostasis and liver regeneration.Our findings identify a highly regulated atypical SUMO conjugation motif that serves to coordinate FXR transcriptional competence,thereby expanding the intricate dynamics of the SUMOylation process used by incoming signals to govern metabolic gene regulation.