2. Academic Validation
  3. Mammalian IRE1α dynamically and functionally coalesces with stress granules

Mammalian IRE1α dynamically and functionally coalesces with stress granules

  • Nat Cell Biol. 2024 May 7. doi: 10.1038/s41556-024-01418-7.
Songzi Liu # 1,  Xiaoge Zhang # 1,  Xin Yao # 1,  Guan Wang 2 3,  Shijia Huang 1,  Peng Chen 1,  Mingliang Tang 1,  Jie Cai 1 4,  Zhuyin Wu 1,  Yiliang Zhang 1,  Rongzhi Xu 1,  Kai Liu 1,  Kangmin He 5 6,  Yan Wang 1,  Lei Jiang 2 3,  Qiong A Wang 2 3,  Liangyou Rui 7,  Jianmiao Liu 8,  Yong Liu 9
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences; TaiKang Center for Life and Medical Sciences; the Institute for Advanced Studies; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
  • 2 Comprehensive Cancer Center, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
  • 3 Department of Molecular & Cellular Endocrinology, Diabetes & Metabolism Research Institute, City of Hope Medical Center, Duarte, CA, USA.
  • 4 Clinical Research Center, the Affiliated Hospital of Guizhou Medical University, Guiyang, China.
  • 5 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  • 6 University of Chinese Academy of Sciences, Beijing, China.
  • 7 Department of Molecular and Integrative Physiology, the University of Michigan Medical School, Ann Arbor, MI, USA.
  • 8 Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology, Wuhan, China.
  • 9 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences; TaiKang Center for Life and Medical Sciences; the Institute for Advanced Studies; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China. [email protected].
  • # Contributed equally.
PMID: 38714852 DOI: 10.1038/s41556-024-01418-7
Abstract

Upon endoplasmic reticulum (ER) stress, activation of the ER-resident transmembrane protein kinase/endoribonuclease inositol-requiring Enzyme 1 (IRE1) initiates a key branch of the unfolded protein response (UPR) through unconventional splicing generation of the transcription factor X-box-binding protein 1 (XBP1s). Activated IRE1 can form large clusters/foci, whose exact dynamic architectures and functional properties remain largely elusive. Here we report that, in mammalian cells, formation of IRE1α clusters is an ER membrane-bound phase separation event that is coupled to the assembly of stress granules (SGs). In response to different stressors, IRE1α clusters are dynamically tethered to SGs at the ER. The cytosolic linker portion of IRE1α possesses intrinsically disordered regions and is essential for its condensation with SGs. Furthermore, disruption of SG assembly abolishes IRE1α clustering and compromises XBP1 mRNA splicing, and such IRE1α-SG coalescence engenders enrichment of the biochemical components of the pro-survival IRE1α-XBP1 pathway during ER stress. Our findings unravel a phase transition mechanism for the spatiotemporal assembly of IRE1α-SG condensates to establish a more efficient IRE1α machinery, thus enabling higher stress-handling capacity.

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