The HRD1-SEL1L ubiquitin ligase regulates stress granule homeostasis in couple with distinctive signaling branches of ER stress

• Published in: iScience Vol. 27; no. 7; p. 110196
• Main Authors: Shi, Wenbo, Ding, Ran, Chen, Yilin, Ji, Fubo, Ji, Junfang, Ma, Weirui, Jin, Jianping
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 19.07.2024; Elsevier
• Subjects: Cell biology; Cellular physiology; Functional aspects of cell biology; Cell biology; Cellular physiology; Functional aspects of cell biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.110196

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. [Display omitted] •HRD1-SEL1L ubiquitin ligase regulates heat shock-induced SG homeostasis specifically•Distinct ER stress branches play differential roles in SG homeostasis•The HRD1-SEL1L complex mediates SG homeostasis via the BiP-PERK-eIF2α signaling axis Cell biology; Cellular physiology; Functional aspects of cell biology