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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\u00a0and provides a roadmap for treating neurodegenerative diseases caused by mitochondrial import defects.\n                  <\/jats:p>","DOI":"10.1038\/s41586-023-06985-7","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T12:02:59Z","timestamp":1706702579000},"page":"874-880","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":122,"title":["Stress response silencing by an E3 ligase mutated in neurodegeneration"],"prefix":"10.1038","volume":"626","author":[{"given":"Diane L.","family":"Haakonsen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Heider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2796-0779","authenticated-orcid":false,"given":"Andrew J.","family":"Ingersoll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9386-2854","authenticated-orcid":false,"given":"Kayla","family":"Vodehnal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel R.","family":"Witus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Uenaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5309-515X","authenticated-orcid":false,"given":"Marius","family":"Wernig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4849-6343","authenticated-orcid":false,"given":"Michael","family":"Rap\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,31]]},"reference":[{"key":"6985_CR1","doi-asserted-by":"publisher","first-page":"eaat5314","DOI":"10.1126\/science.aat5314","volume":"368","author":"M Costa-Mattioli","year":"2020","unstructured":"Costa-Mattioli, M. & Walter, P. 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