Cargando…
A translational program that suppresses metabolism to shield the genome
Translatome reprogramming is a primary determinant of protein levels during stimuli adaptation. This raises the question: what are the translatome remodelers that reprogram protein output to activate biochemical adaptations. Here, we identify a translational pathway that represses metabolism to safe...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666154/ https://www.ncbi.nlm.nih.gov/pubmed/33188200 http://dx.doi.org/10.1038/s41467-020-19602-2 |
_version_ | 1783610078676385792 |
---|---|
author | Balukoff, Nathan C. Ho, J. J. David Theodoridis, Phaedra R. Wang, Miling Bokros, Michael Llanio, Lis M. Krieger, Jonathan R. Schatz, Jonathan H. Lee, Stephen |
author_facet | Balukoff, Nathan C. Ho, J. J. David Theodoridis, Phaedra R. Wang, Miling Bokros, Michael Llanio, Lis M. Krieger, Jonathan R. Schatz, Jonathan H. Lee, Stephen |
author_sort | Balukoff, Nathan C. |
collection | PubMed |
description | Translatome reprogramming is a primary determinant of protein levels during stimuli adaptation. This raises the question: what are the translatome remodelers that reprogram protein output to activate biochemical adaptations. Here, we identify a translational pathway that represses metabolism to safeguard genome integrity. A system-wide MATRIX survey identified the ancient eIF5A as a pH-regulated translation factor that responds to fermentation-induced acidosis. TMT-pulse-SILAC analysis identified several pH-dependent proteins, including the mTORC1 suppressor Tsc2 and the longevity regulator Sirt1. Sirt1 operates as a pH-sensor that deacetylates nuclear eIF5A during anaerobiosis, enabling the cytoplasmic export of eIF5A/Tsc2 mRNA complexes for translational engagement. Tsc2 induction inhibits mTORC1 to suppress cellular metabolism and prevent acidosis-induced DNA damage. Depletion of eIF5A or Tsc2 leads to metabolic re-initiation and proliferation, but at the expense of incurring substantial DNA damage. We suggest that eIF5A operates as a translatome remodeler that suppresses metabolism to shield the genome. |
format | Online Article Text |
id | pubmed-7666154 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76661542020-11-17 A translational program that suppresses metabolism to shield the genome Balukoff, Nathan C. Ho, J. J. David Theodoridis, Phaedra R. Wang, Miling Bokros, Michael Llanio, Lis M. Krieger, Jonathan R. Schatz, Jonathan H. Lee, Stephen Nat Commun Article Translatome reprogramming is a primary determinant of protein levels during stimuli adaptation. This raises the question: what are the translatome remodelers that reprogram protein output to activate biochemical adaptations. Here, we identify a translational pathway that represses metabolism to safeguard genome integrity. A system-wide MATRIX survey identified the ancient eIF5A as a pH-regulated translation factor that responds to fermentation-induced acidosis. TMT-pulse-SILAC analysis identified several pH-dependent proteins, including the mTORC1 suppressor Tsc2 and the longevity regulator Sirt1. Sirt1 operates as a pH-sensor that deacetylates nuclear eIF5A during anaerobiosis, enabling the cytoplasmic export of eIF5A/Tsc2 mRNA complexes for translational engagement. Tsc2 induction inhibits mTORC1 to suppress cellular metabolism and prevent acidosis-induced DNA damage. Depletion of eIF5A or Tsc2 leads to metabolic re-initiation and proliferation, but at the expense of incurring substantial DNA damage. We suggest that eIF5A operates as a translatome remodeler that suppresses metabolism to shield the genome. Nature Publishing Group UK 2020-11-13 /pmc/articles/PMC7666154/ /pubmed/33188200 http://dx.doi.org/10.1038/s41467-020-19602-2 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Balukoff, Nathan C. Ho, J. J. David Theodoridis, Phaedra R. Wang, Miling Bokros, Michael Llanio, Lis M. Krieger, Jonathan R. Schatz, Jonathan H. Lee, Stephen A translational program that suppresses metabolism to shield the genome |
title | A translational program that suppresses metabolism to shield the genome |
title_full | A translational program that suppresses metabolism to shield the genome |
title_fullStr | A translational program that suppresses metabolism to shield the genome |
title_full_unstemmed | A translational program that suppresses metabolism to shield the genome |
title_short | A translational program that suppresses metabolism to shield the genome |
title_sort | translational program that suppresses metabolism to shield the genome |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666154/ https://www.ncbi.nlm.nih.gov/pubmed/33188200 http://dx.doi.org/10.1038/s41467-020-19602-2 |
work_keys_str_mv | AT balukoffnathanc atranslationalprogramthatsuppressesmetabolismtoshieldthegenome AT hojjdavid atranslationalprogramthatsuppressesmetabolismtoshieldthegenome AT theodoridisphaedrar atranslationalprogramthatsuppressesmetabolismtoshieldthegenome AT wangmiling atranslationalprogramthatsuppressesmetabolismtoshieldthegenome AT bokrosmichael atranslationalprogramthatsuppressesmetabolismtoshieldthegenome AT llaniolism atranslationalprogramthatsuppressesmetabolismtoshieldthegenome AT kriegerjonathanr atranslationalprogramthatsuppressesmetabolismtoshieldthegenome AT schatzjonathanh atranslationalprogramthatsuppressesmetabolismtoshieldthegenome AT leestephen atranslationalprogramthatsuppressesmetabolismtoshieldthegenome AT balukoffnathanc translationalprogramthatsuppressesmetabolismtoshieldthegenome AT hojjdavid translationalprogramthatsuppressesmetabolismtoshieldthegenome AT theodoridisphaedrar translationalprogramthatsuppressesmetabolismtoshieldthegenome AT wangmiling translationalprogramthatsuppressesmetabolismtoshieldthegenome AT bokrosmichael translationalprogramthatsuppressesmetabolismtoshieldthegenome AT llaniolism translationalprogramthatsuppressesmetabolismtoshieldthegenome AT kriegerjonathanr translationalprogramthatsuppressesmetabolismtoshieldthegenome AT schatzjonathanh translationalprogramthatsuppressesmetabolismtoshieldthegenome AT leestephen translationalprogramthatsuppressesmetabolismtoshieldthegenome |