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
  • 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. [email protected].
  • 6. Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA. [email protected].
  • 7. California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, CA, USA. [email protected].
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.

Products