Shi Wenbo, Ding Ran, Chen Yilin, Ji Fubo, Ji Junfang, Ma Weirui, Jin Jianping
Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing 321000, China.
iScience. 2024 Jun 6;27(7):110196. doi: 10.1016/j.isci.2024.110196. eCollection 2024 Jul 19.
Stress granules (SGs) are membrane-less cellular compartments which are dynamically assembled via biomolecular condensation mechanism when eukaryotic cells encounter environmental stresses. SGs are important for gene expression and cell fate regulation. Dysregulation of SG homeostasis has been linked to human neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we report that the HRD1-SEL1L ubiquitin ligase complex specifically regulates the homeostasis of heat shock-induced SGs through the ubiquitin-proteasome system (UPS) and the UPS-associated ATPase p97. Mechanistically, the HRD1-SEL1L complex mediates SG homeostasis through the BiP-coupled PERK-eIF2α signaling axis of endoplasmic reticulum (ER) stress, thereby coordinating the unfolded protein response (UPR) with SG dynamics. Furthermore, we show that the distinctive branches of ER stress play differential roles in SG homeostasis. Our study indicates that the UPS and the UPR together via the HRD1-SEL1L ubiquitin ligase to maintain SG homeostasis in a stressor-dependent manner.
应激颗粒（SGs）是无膜的细胞区室，当真核细胞遇到环境应激时，它们通过生物分子凝聚机制动态组装。应激颗粒对于基因表达和细胞命运调控很重要。应激颗粒稳态失调与人类神经退行性疾病有关，包括肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）。在此，我们报告HRD1-SEL1L泛素连接酶复合物通过泛素-蛋白酶体系统（UPS）和与UPS相关的ATP酶p97特异性调节热休克诱导的应激颗粒的稳态。从机制上讲，HRD1-SEL1L复合物通过内质网（ER）应激的BiP偶联的PERK-eIF2α信号轴介导应激颗粒稳态，从而协调未折叠蛋白反应（UPR）与应激颗粒动态变化。此外，我们表明内质网应激的不同分支在应激颗粒稳态中发挥不同作用。我们的研究表明，UPS和UPR通过HRD1-SEL1L泛素连接酶共同以应激源依赖的方式维持应激颗粒稳态。
