In:
Nature, Springer Science and Business Media LLC, Vol. 626, No. 8000 ( 2024-02-22), p. 874-880
Abstract:
Stress response pathways detect and alleviate adverse conditions to safeguard cell and tissue homeostasis, yet their prolonged activation induces apoptosis and disrupts organismal health 1–3 . 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.
Type of Medium:
Online Resource
ISSN:
0028-0836
,
1476-4687
DOI:
10.1038/s41586-023-06985-7
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2024
detail.hit.zdb_id:
120714-3
detail.hit.zdb_id:
1413423-8
SSG:
11
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