2. Academic Validation
  3. Stress response silencing by an E3 ligase mutated in neurodegeneration

Stress response silencing by an E3 ligase mutated in neurodegeneration

  • Nature. 2024 Jan 31. doi: 10.1038/s41586-023-06985-7.
Diane L Haakonsen 1 2,  Michael Heider 1,  Andrew J Ingersoll 1,  Kayla Vodehnal 3 4,  Samuel R Witus 1 2,  Takeshi Uenaka 3 4,  Marius Wernig 3 4,  Michael Rapé 5 6 7
Affiliations

Affiliations

  • 1 Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA.
  • 2 Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA.
  • 3 Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • 4 Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • 5 Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA. mrape@berkeley.edu.
  • 6 Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA. mrape@berkeley.edu.
  • 7 California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, CA, USA. mrape@berkeley.edu.
PMID: 38297121 DOI: 10.1038/s41586-023-06985-7
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.

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