摘要
Farnesoid X 受体(FXR ) 是在调整涉及胆汁酸动态平衡，和脂肪和葡萄糖新陈代谢的基因起一个中央作用的激活 ligand 的原子受体。这里，我们表明在在 hepatocytes 指导受体进一条激活降级小径的 FXR phosphorylation， SUMOylation，和 ubiquitination 之间的 translational 以后相互影响。我们识别一个不在经典中的 SUMOylation 主题在酷蛋白 kinase 的直接控制下面在 FXR 的 Lys-325 结合 SUMO2 的称为的 pSuM 2 (CK2 ) ，它提供要求的否定费用让 Ubc9 和 PIAS1 执行 SUMOylation，由 phosphorylating Ser-327。Lys-325 SUMOylation 对有效 ligand 激活的提升和 FXR 的 transcriptional coactivation 不可缺少。用 phospho 模仿 Ser-327 变异或催化的 CK2 表情的组成的 pSuM 激活强烈导致 SUMO2 变化形式，它指导 FXR ubiquitination 和 proteasome 依赖的降级。我们也决定 FXR 的如此的 SUMOylation 依赖的 ubiquitination 被 E3 ubiquitin ligase RNF4 调停，它被要求完成 FXR 的最大的正式就职并且在上面最佳 -- 或涉及胆汁酸动态平衡和肝新生的应答的基因的 downregulation。我们的调查结果识别服务协调 FXR transcriptional 胜任的一个高度调整的不正常的相扑变化形式主题，从而扩展到来的信号过去常管理新陈代谢的基因规定的 SUMOylation 过程的复杂动力学。
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 phosphoryl- ation, SUMOylation, and ubiquitination that directs the receptor into an activation-degradation pathway in hepatocytes. We iden- tify a non-canonical SUMOylation motif termed pSuM that conjugates SUM02 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 SUM02 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 compe- tence, thereby expanding the intricate dynamics of the SUMOylation process used by incoming signals to govern metabolic gene regulation.
