Open AccessAn infection-induced oxidation site regulates legumain processing and tumor growth
Author(s) -
Yekaterina Kovalyova,
Daniel W. Bak,
Elizabeth M. Gordon,
Connie Fung,
Jennifer H. B. Shuman,
Timothy L. Cover,
Manuel R. Amieva,
Eranthie Weerapana,
Stavroula K. Hatzios
Publication year - 2022
Publication title -
nature chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.412
H-Index - 216
eISSN - 1552-4469
pISSN - 1552-4450
DOI - 10.1038/s41589-022-00992-x
Subject(s) - carcinogenesis , cysteine , biology , oxidative stress , reactive oxygen species , enzyme , chemistry , cancer research , biochemistry , gene
Oxidative stress is a defining feature of most cancers, including those that stem from carcinogenic infections. Reactive oxygen species can drive tumor formation, 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.