Cargando…
C16orf72/HAPSTR1 is a molecular rheostat in an integrated network of stress response pathways
All cells contain specialized signaling pathways that enable adaptation to specific molecular stressors. Yet, whether these pathways are centrally regulated in complex physiological stress states remains unclear. Using genome-scale fitness screening data, we quantified the stress phenotype of 739 ca...
Autores principales: | , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9271168/ https://www.ncbi.nlm.nih.gov/pubmed/35776542 http://dx.doi.org/10.1073/pnas.2111262119 |
_version_ | 1784744620526141440 |
---|---|
author | Amici, David R. Ansel, Daniel J. Metz, Kyle A. Smith, Roger S. Phoumyvong, Claire M. Gayatri, Sitaram Chamera, Tomasz Edwards, Stacey L. O’Hara, Brendan P. Srivastava, Shashank Brockway, Sonia Takagishi, Seesha R. Cho, Byoung-Kyu Goo, Young Ah Kelleher, Neil L. Ben-Sahra, Issam Foltz, Daniel R. Li, Jian Mendillo, Marc L. |
author_facet | Amici, David R. Ansel, Daniel J. Metz, Kyle A. Smith, Roger S. Phoumyvong, Claire M. Gayatri, Sitaram Chamera, Tomasz Edwards, Stacey L. O’Hara, Brendan P. Srivastava, Shashank Brockway, Sonia Takagishi, Seesha R. Cho, Byoung-Kyu Goo, Young Ah Kelleher, Neil L. Ben-Sahra, Issam Foltz, Daniel R. Li, Jian Mendillo, Marc L. |
author_sort | Amici, David R. |
collection | PubMed |
description | All cells contain specialized signaling pathways that enable adaptation to specific molecular stressors. Yet, whether these pathways are centrally regulated in complex physiological stress states remains unclear. Using genome-scale fitness screening data, we quantified the stress phenotype of 739 cancer cell lines, each representing a unique combination of intrinsic tumor stresses. Integrating dependency and stress perturbation transcriptomic data, we illuminated a network of genes with vital functions spanning diverse stress contexts. Analyses for central regulators of this network nominated C16orf72/HAPSTR1, an evolutionarily ancient gene critical for the fitness of cells reliant on multiple stress response pathways. We found that HAPSTR1 plays a pleiotropic role in cellular stress signaling, functioning to titrate various specialized cell-autonomous and paracrine stress response programs. This function, while dispensable to unstressed cells and nematodes, is essential for resilience in the presence of stressors ranging from DNA damage to starvation and proteotoxicity. Mechanistically, diverse stresses induce HAPSTR1, which encodes a protein expressed as two equally abundant isoforms. Perfectly conserved residues in a domain shared between HAPSTR1 isoforms mediate oligomerization and binding to the ubiquitin ligase HUWE1. We show that HUWE1 is a required cofactor for HAPSTR1 to control stress signaling and that, in turn, HUWE1 feeds back to ubiquitinate and destabilize HAPSTR1. Altogether, we propose that HAPSTR1 is a central rheostat in a network of pathways responsible for cellular adaptability, the modulation of which may have broad utility in human disease. |
format | Online Article Text |
id | pubmed-9271168 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-92711682022-07-11 C16orf72/HAPSTR1 is a molecular rheostat in an integrated network of stress response pathways Amici, David R. Ansel, Daniel J. Metz, Kyle A. Smith, Roger S. Phoumyvong, Claire M. Gayatri, Sitaram Chamera, Tomasz Edwards, Stacey L. O’Hara, Brendan P. Srivastava, Shashank Brockway, Sonia Takagishi, Seesha R. Cho, Byoung-Kyu Goo, Young Ah Kelleher, Neil L. Ben-Sahra, Issam Foltz, Daniel R. Li, Jian Mendillo, Marc L. Proc Natl Acad Sci U S A Biological Sciences All cells contain specialized signaling pathways that enable adaptation to specific molecular stressors. Yet, whether these pathways are centrally regulated in complex physiological stress states remains unclear. Using genome-scale fitness screening data, we quantified the stress phenotype of 739 cancer cell lines, each representing a unique combination of intrinsic tumor stresses. Integrating dependency and stress perturbation transcriptomic data, we illuminated a network of genes with vital functions spanning diverse stress contexts. Analyses for central regulators of this network nominated C16orf72/HAPSTR1, an evolutionarily ancient gene critical for the fitness of cells reliant on multiple stress response pathways. We found that HAPSTR1 plays a pleiotropic role in cellular stress signaling, functioning to titrate various specialized cell-autonomous and paracrine stress response programs. This function, while dispensable to unstressed cells and nematodes, is essential for resilience in the presence of stressors ranging from DNA damage to starvation and proteotoxicity. Mechanistically, diverse stresses induce HAPSTR1, which encodes a protein expressed as two equally abundant isoforms. Perfectly conserved residues in a domain shared between HAPSTR1 isoforms mediate oligomerization and binding to the ubiquitin ligase HUWE1. We show that HUWE1 is a required cofactor for HAPSTR1 to control stress signaling and that, in turn, HUWE1 feeds back to ubiquitinate and destabilize HAPSTR1. Altogether, we propose that HAPSTR1 is a central rheostat in a network of pathways responsible for cellular adaptability, the modulation of which may have broad utility in human disease. National Academy of Sciences 2022-07-01 2022-07-05 /pmc/articles/PMC9271168/ /pubmed/35776542 http://dx.doi.org/10.1073/pnas.2111262119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Amici, David R. Ansel, Daniel J. Metz, Kyle A. Smith, Roger S. Phoumyvong, Claire M. Gayatri, Sitaram Chamera, Tomasz Edwards, Stacey L. O’Hara, Brendan P. Srivastava, Shashank Brockway, Sonia Takagishi, Seesha R. Cho, Byoung-Kyu Goo, Young Ah Kelleher, Neil L. Ben-Sahra, Issam Foltz, Daniel R. Li, Jian Mendillo, Marc L. C16orf72/HAPSTR1 is a molecular rheostat in an integrated network of stress response pathways |
title | C16orf72/HAPSTR1 is a molecular rheostat in an integrated network of stress response pathways |
title_full | C16orf72/HAPSTR1 is a molecular rheostat in an integrated network of stress response pathways |
title_fullStr | C16orf72/HAPSTR1 is a molecular rheostat in an integrated network of stress response pathways |
title_full_unstemmed | C16orf72/HAPSTR1 is a molecular rheostat in an integrated network of stress response pathways |
title_short | C16orf72/HAPSTR1 is a molecular rheostat in an integrated network of stress response pathways |
title_sort | c16orf72/hapstr1 is a molecular rheostat in an integrated network of stress response pathways |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9271168/ https://www.ncbi.nlm.nih.gov/pubmed/35776542 http://dx.doi.org/10.1073/pnas.2111262119 |
work_keys_str_mv | AT amicidavidr c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT anseldanielj c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT metzkylea c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT smithrogers c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT phoumyvongclairem c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT gayatrisitaram c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT chameratomasz c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT edwardsstaceyl c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT oharabrendanp c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT srivastavashashank c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT brockwaysonia c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT takagishiseeshar c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT chobyoungkyu c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT gooyoungah c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT kelleherneill c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT bensahraissam c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT foltzdanielr c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT lijian c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways AT mendillomarcl c16orf72hapstr1isamolecularrheostatinanintegratednetworkofstressresponsepathways |