Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Stockholm, Sweden.
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
EMBO J. 2023 Feb 1;42(3):e111802. doi: 10.15252/embj.2022111802. Epub 2022 Dec 27.
The role of cytosolic stress granules in the integrated stress response has remained largely enigmatic. Here, we studied the functionality of the ubiquitin-proteasome system (UPS) in cells that were unable to form stress granules. Surprisingly, the inability of cells to form cytosolic stress granules had primarily a negative impact on the functionality of the nuclear UPS. While defective ribosome products (DRiPs) accumulated at stress granules in thermally stressed control cells, they localized to nucleoli in stress granule-deficient cells. The nuclear localization of DRiPs was accompanied by redistribution and enhanced degradation of SUMOylated proteins. Depletion of the SUMO-targeted ubiquitin ligase RNF4, which targets SUMOylated misfolded proteins for proteasomal degradation, largely restored the functionality of the UPS in the nuclear compartment in stress granule-deficient cells. Stress granule-deficient cells showed an increase in the formation of mutant ataxin-1 nuclear inclusions when exposed to thermal stress. Our data reveal that stress granules play an important role in the sequestration of cytosolic misfolded proteins, thereby preventing these proteins from accumulating in the nucleus, where they would otherwise infringe nuclear proteostasis.
细胞质应激颗粒在整合应激反应中的作用在很大程度上仍然是个谜。在这里，我们研究了在不能形成细胞质应激颗粒的细胞中泛素-蛋白酶体系统 (UPS) 的功能。令人惊讶的是，细胞不能形成细胞质应激颗粒主要对核 UPS 的功能产生负面影响。虽然热应激对照细胞中的应激颗粒中积累了有缺陷的核糖体产物 (DRiPs)，但它们在应激颗粒缺陷细胞中定位于核仁。DRiPs 的核定位伴随着 SUMO 化蛋白的重新分布和增强的降解。耗尽 SUMO 靶向泛素连接酶 RNF4（该酶将 SUMO 化错误折叠的蛋白质靶向蛋白酶体降解），在应激颗粒缺陷细胞中，核 UPS 的功能在很大程度上得到了恢复。应激颗粒缺陷细胞在暴露于热应激时形成突变的共济失调蛋白-1 核内包涵体的数量增加。我们的数据表明，应激颗粒在隔离细胞质中错误折叠的蛋白质方面发挥着重要作用，从而防止这些蛋白质在核内积累，否则它们会破坏核内蛋白质稳态。
