Helicobacter pylori pathogen inhibits cellular responses to oncogenic stress and apoptosis.

Manikandan Palrasu, Elena Zaika, Kodisundaram Paulrasu, Ravindran Caspa Gokulan, Giovanni Suarez, Jianwen Que, Wael El-Rifai, Richard M Peek, Monica Garcia-Buitrago, Alexander I Zaika

PLoS pathogens 2022 Jun

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Helicobacter pylori (H. pylori) is a common gastric pathogen that infects approximately half of the world's population. Infection with H. pylori can lead to diverse pathological conditions, including chronic gastritis, peptic ulcer disease, and cancer. The latter is the most severe consequence of H. pylori infection. According to epidemiological studies, gastric infection with H. pylori is the strongest known risk factor for non-cardia gastric cancer (GC), which remains one of the leading causes of cancer-related deaths worldwide. However, it still remains to be poorly understood how host-microbe interactions result in cancer development in the human stomach. Here we focus on the H. pylori bacterial factors that affect the host ubiquitin proteasome system. We investigated E3 ubiquitin ligases SIVA1 and ULF that regulate p14ARF (p19ARF in mice) tumor suppressor. ARF plays a key role in regulation of the oncogenic stress response and is frequently inhibited during GC progression. Expression of ARF, SIVA1 and ULF proteins were investigated in gastroids, H. pylori-infected mice and human gastric tissues. The role of the H. pylori type IV secretion system was assessed using various H. pylori isogenic mutants. Our studies demonstrated that H. pylori infection results in induction of ULF, decrease in SIVA1 protein levels, and subsequent ubiquitination and degradation of p14ARF tumor suppressor. Bacterial CagA protein was found to sequentially bind to SIVA1 and ULF proteins. This process is regulated by CagA protein phosphorylation at the EPIYA motifs. Downregulation of ARF protein leads to inhibition of cellular apoptosis and oncogenic stress response that may promote gastric carcinogenesis.

Citation

Manikandan Palrasu, Elena Zaika, Kodisundaram Paulrasu, Ravindran Caspa Gokulan, Giovanni Suarez, Jianwen Que, Wael El-Rifai, Richard M Peek, Monica Garcia-Buitrago, Alexander I Zaika. Helicobacter pylori pathogen inhibits cellular responses to oncogenic stress and apoptosis. PLoS pathogens. 2022 Jun;18(6):e1010628