Stress response silencing by an E3 ligase mutated in neurodegeneration

Diane L. Haakonsen, Michael Heider, Andrew J. Ingersoll, Kayla Vodehnal, Samuel R. Witus, Takeshi Uenaka, Marius Wernig and Michael Rapé ()
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Diane L. Haakonsen: University of California at Berkeley
Michael Heider: University of California at Berkeley
Andrew J. Ingersoll: University of California at Berkeley
Kayla Vodehnal: Stanford University School of Medicine
Samuel R. Witus: University of California at Berkeley
Takeshi Uenaka: Stanford University School of Medicine
Marius Wernig: Stanford University School of Medicine
Michael Rapé: University of California at Berkeley

Nature, 2024, vol. 626, issue 8000, 874-880

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-023-06985-7

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