The Nuclear SUMO-Targeted Ubiquitin Quality Control Network Regulates the Dynamics of Cytoplasmic Stress Granules
The Nuclear SUMO-Targeted Ubiquitin Quality Control Network Regulates the Dynamics of Cytoplasmic Stress Granules
复制标题
DOI：
10.1016/j.molcel.2020.05.017
复制
发表时间：
2020-07-02
期刊：
影响因子：
16
通讯作者：
Mueller, Stefan
中科院分区：
文献类型：
--
作者：
Keiten-Schmitz, Jan;Wagner, Kristina;Mueller, Stefan
细胞暴露在高温或氧化应激下会导致蛋白质的错误折叠。为了避免有毒的蛋白质聚集，细胞进化了核蛋白和胞质蛋白质量控制(PQC)系统。作为对蛋白毒性应激的响应，细胞还通过触发mRNAs和RNA结合蛋白(RBP)在胞浆应激颗粒(SGS)中的瞬时存储来限制蛋白质的合成。我们证明，相扑靶向泛素连接酶(StUbL)通路是核蛋白平衡网络的一部分，调节SG的动力学。我们提供的证据表明，在蛋白毒性应激下，相扑去结合气体的失活启动了相扑启动的、RNF4依赖的限制性商业惯例泛素化，这些泛素化通常会缩合成SGS。相扑启动泛素化的损伤在压力释放时显著延迟SG的分解。重要的是，StUbL系统调节SGS中与肌萎缩侧索硬化症(ALS)相关的FUS突变体的区划。我们认为StUbL系统可以作为核内易于聚集的限制性商业惯例的监视途径，从而连接蛋白毒性应激反应的核轴和胞质轴。
Exposure of cells to heat or oxidative stress causes misfolding of proteins. To avoid toxic protein aggregation, cells have evolved nuclear and cytosolic protein quality control (PQC) systems. In response to proteotoxic stress, cells also limit protein synthesis by triggering transient storage of mRNAs and RNA-binding proteins (RBPs) in cytosolic stress granules (SGs). We demonstrate that the SUMO-targeted ubiquitin ligase (StUbL) pathway, which is part of the nuclear proteostasis network, regulates SG dynamics. We provide evidence that inactivation of SUMO deconjugases under proteotoxic stress initiates SUMO-primed, RNF4-dependent ubiquitylation of RBPs that typically condense into SGs. Impairment of SUMO-primed ubiquitylation drastically delays SG resolution upon stress release. Importantly, the StUbL system regulates compartmentalization of an amyotrophic lateral sclerosis (ALS)-associated FUS mutant in SGs. We propose that the StUbL system functions as surveillance pathway for aggregation-prone RBPs in the nucleus, thereby linking the nuclear and cytosolic axis of proteotoxic stress response.