Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
Nat Commun. 2016 Jul 14;7:12179. doi: 10.1038/ncomms12179.
Bile acids (BAs) are recently recognized signalling molecules that profoundly affect metabolism. Because of detergent-like toxicity, BA levels must be tightly regulated. An orphan nuclear receptor, Small Heterodimer Partner (SHP), plays a key role in this regulation, but how SHP senses the BA signal for feedback transcriptional responses is not clearly understood. We show an unexpected function of a nucleoporin, RanBP2, in maintaining BA homoeostasis through SUMOylation of SHP. Upon BA signalling, RanBP2 co-localizes with SHP at the nuclear envelope region and mediates SUMO2 modification at K68, which facilitates nuclear transport of SHP and its interaction with repressive histone modifiers to inhibit BA synthetic genes. Mice expressing a SUMO-defective K68R SHP mutant have increased liver BA levels, and upon BA- or drug-induced biliary insults, these mice exhibit exacerbated cholestatic pathologies. These results demonstrate a function of RanBP2-mediated SUMOylation of SHP in maintaining BA homoeostasis and protecting from the BA hepatotoxicity.
胆汁酸（BAs）是最近被认为具有信号作用的分子，可深刻影响代谢。由于具有去污剂样毒性，BAs 水平必须受到严格调控。孤儿核受体小异二聚体伴侣（SHP）在这种调控中发挥关键作用，但 SHP 如何感知 BA 信号以进行反馈转录反应尚不清楚。我们发现核孔蛋白 RanBP2 通过对 SHP 的 SUMO 化在维持 BA 动态平衡方面具有意想不到的功能。在 BA 信号转导时，RanBP2 与 SHP 在核膜区域共定位，并介导 K68 的 SUMO2 修饰，这有利于 SHP 的核转运及其与抑制性组蛋白修饰物的相互作用，以抑制 BA 合成基因。表达 SUMO 缺陷 K68R SHP 突变体的小鼠肝脏 BA 水平升高，并且在 BA 或药物诱导的胆汁淤积性损伤时，这些小鼠表现出更严重的胆汁淤积性病理。这些结果表明，RanBP2 介导的 SHP SUMO 化在维持 BA 动态平衡和防止 BA 肝毒性方面具有功能。
