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An infection-induced oxidation site regulates legumain processing and tumor growth

Oxidative stress is a defining feature of most cancers, including those that stem from carcinogenic infections(1). Reactive oxygen species (ROS) can drive tumor formation(2–4), yet the molecular oxidation events that contribute to tumorigenesis are largely unknown. Here we show that inactivation of...

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Autores principales: Kovalyova, Yekaterina, Bak, Daniel W., Gordon, Elizabeth M., Fung, Connie, Shuman, Jennifer H. B., Cover, Timothy L., Amieva, Manuel R., Weerapana, Eranthie, Hatzios, Stavroula K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9246868/
https://www.ncbi.nlm.nih.gov/pubmed/35332331
http://dx.doi.org/10.1038/s41589-022-00992-x
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author Kovalyova, Yekaterina
Bak, Daniel W.
Gordon, Elizabeth M.
Fung, Connie
Shuman, Jennifer H. B.
Cover, Timothy L.
Amieva, Manuel R.
Weerapana, Eranthie
Hatzios, Stavroula K.
author_facet Kovalyova, Yekaterina
Bak, Daniel W.
Gordon, Elizabeth M.
Fung, Connie
Shuman, Jennifer H. B.
Cover, Timothy L.
Amieva, Manuel R.
Weerapana, Eranthie
Hatzios, Stavroula K.
author_sort Kovalyova, Yekaterina
collection PubMed
description Oxidative stress is a defining feature of most cancers, including those that stem from carcinogenic infections(1). Reactive oxygen species (ROS) can drive tumor formation(2–4), yet the molecular oxidation events that contribute to tumorigenesis are largely unknown. Here we show that inactivation of a single, redox-sensitive cysteine in the host protease legumain, which is oxidized during infection with the gastric cancer-causing bacterium Helicobacter pylori, accelerates tumor growth. By using chemical proteomics to map cysteine reactivity in human gastric cells, we determined that H. pylori infection induces oxidation of legumain at Cys219. Legumain oxidation dysregulates intracellular legumain processing and decreases the activity of the enzyme in H. pylori-infected cells. We further show that the site-specific loss of Cys219 reactivity increases tumor growth and mortality in a xenograft model. Our findings establish a link between an infection-induced oxidation site and tumorigenesis while underscoring the importance of cysteine reactivity in tumor growth.
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spelling pubmed-92468682022-09-24 An infection-induced oxidation site regulates legumain processing and tumor growth Kovalyova, Yekaterina Bak, Daniel W. Gordon, Elizabeth M. Fung, Connie Shuman, Jennifer H. B. Cover, Timothy L. Amieva, Manuel R. Weerapana, Eranthie Hatzios, Stavroula K. Nat Chem Biol Article Oxidative stress is a defining feature of most cancers, including those that stem from carcinogenic infections(1). Reactive oxygen species (ROS) can drive tumor formation(2–4), yet the molecular oxidation events that contribute to tumorigenesis are largely unknown. Here we show that inactivation of a single, redox-sensitive cysteine in the host protease legumain, which is oxidized during infection with the gastric cancer-causing bacterium Helicobacter pylori, accelerates tumor growth. By using chemical proteomics to map cysteine reactivity in human gastric cells, we determined that H. pylori infection induces oxidation of legumain at Cys219. Legumain oxidation dysregulates intracellular legumain processing and decreases the activity of the enzyme in H. pylori-infected cells. We further show that the site-specific loss of Cys219 reactivity increases tumor growth and mortality in a xenograft model. Our findings establish a link between an infection-induced oxidation site and tumorigenesis while underscoring the importance of cysteine reactivity in tumor growth. 2022-07 2022-03-24 /pmc/articles/PMC9246868/ /pubmed/35332331 http://dx.doi.org/10.1038/s41589-022-00992-x Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Kovalyova, Yekaterina
Bak, Daniel W.
Gordon, Elizabeth M.
Fung, Connie
Shuman, Jennifer H. B.
Cover, Timothy L.
Amieva, Manuel R.
Weerapana, Eranthie
Hatzios, Stavroula K.
An infection-induced oxidation site regulates legumain processing and tumor growth
title An infection-induced oxidation site regulates legumain processing and tumor growth
title_full An infection-induced oxidation site regulates legumain processing and tumor growth
title_fullStr An infection-induced oxidation site regulates legumain processing and tumor growth
title_full_unstemmed An infection-induced oxidation site regulates legumain processing and tumor growth
title_short An infection-induced oxidation site regulates legumain processing and tumor growth
title_sort infection-induced oxidation site regulates legumain processing and tumor growth
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9246868/
https://www.ncbi.nlm.nih.gov/pubmed/35332331
http://dx.doi.org/10.1038/s41589-022-00992-x
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