Helicobacter pylori pathogen inhibits cellular responses to oncogenic stress and apoptosis

Abstract

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. Stomach infection with Helicobacter pylori bacteria is considered to be one of the strongest known risk factors for gastric cancer. Understanding mechanisms regulating carcinogenic interactions between bacteria and human cells is important for development of new effective therapies against gastric cancer. In this work, we report how bacterial protein CagA alters intracellular regulation inside human cells, causing inhibition of tumor suppression mechanism termed the Oncogenic Stress Response controlled by human protein p14ARF. Our studies revealed that bacterial protein CagA interacts with two human proteins SIVA1 and ULF, resulting in activation of ULF and rapid degradation of SIVA1 and p14ARF, which regulate cell death of tumorous cells.