Stress response silencing by an E3 ligase mutated in neurodegeneration

• 成果类型: Article
• 署名作者: Haakonsen, Diane L.; Heider, Michael; Ingersoll, Andrew J.; Vodehnal, Kayla; Witus, Samuel R.; Uenaka, Takeshi; Wernig, Marius; Rape, Michael
• 署名单位: University of California System; University of California Berkeley; University of California System; University of California Berkeley; Howard Hughes Medical Institute; Stanford University; Stanford University; University of California System; University of California Berkeley
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6407
• DOI: 10.1038/s41586-023-06985-7
• 发表日期: 2024-02-22
• 关键词: unfolded protein response; quality-control; n-recognin; er stress; mitochondrial; translation; ubr4; inhibition; activation; mechanism

摘要

Stress response pathways detect and alleviate adverse conditions to safeguard cell and tissue homeostasis, yet their prolonged activation induces apoptosis and disrupts organismal health1-3. How stress responses are turned off at the right time and place remains poorly understood. Here we report a ubiquitin-dependent mechanism that silences the cellular response to mitochondrial protein import stress. Crucial to this process is the silencing factor of the integrated stress response (SIFI), a large E3 ligase complex mutated in ataxia and in early-onset dementia that degrades both unimported mitochondrial precursors and stress response components. By recognizing bifunctional substrate motifs that equally encode protein localization and stability, the SIFI complex turns off a general stress response after a specific stress event has been resolved. Pharmacological stress response silencing sustains cell survival even if stress resolution failed, which underscores the importance of signal termination and provides a roadmap for treating neurodegenerative diseases caused by mitochondrial import defects. The E3 ligase SIFI is identified as a dedicated silencing factor of the integrated stress response, a finding that has implications for the development of therapeutics for neurodegenerative diseases caused by mitochondrial protein import stress.