An infection-activated redox switch promotes tumor growth

Abstract Oxidative stress is a defining feature of most cancers, including those that stem from carcinogenic infections1. Reactive oxygen species (ROS) can drive tumor formation2–4, 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, which is enhanced by the ROS-promoting bacterial oncoprotein CagA, dysregulates intracellular legumain processing and localization and decreases legumain activity 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 the precise oxidation of a host protein and tumorigenic signaling during bacterial infection and demonstrate the importance of oxidative post-translational modifications in tumor growth.