Loss of UBE3C-mediated PIM2 ubiquitination drives Helicobacter pylori-induced gastritis via JAK2/STAT3 activation.

Abstract

Helicobacter pylori (H. pylori) infection is a major cause of chronic gastritis, yet its molecular mechanisms remain incompletely understood. In this study, we found that the proviral integration site for Moloney murine leukemia virus kinase 2 (PIM2) was significantly upregulated in H. pylori-infected gastric tissues and cells. Functionally, PIM2 knockdown not only attenuated inflammatory responses both in vivo and in vitro but also significantly reduced gastric H. pylori colonization in mice. Mechanistically, H. pylori infection downregulated the expression of the E3 ubiquitin ligase UBE3C, leading to decreased ubiquitination of PIM2 at K165 and enhanced PIM2 protein stability. Accumulated PIM2 subsequently activated the JAK2/STAT3 pathway, driving inflammatory responses. Combined treatment with the JAK1/2 inhibitor Ruxolitinib further potentiated the anti-inflammatory effects of PIM2 knockdown in H. pylori-infected GES-1 cells and mouse gastric tissues. This study revealed a novel mechanism by which H. pylori promoted gastritis through downregulation of UBE3C, impairment of PIM2 ubiquitination, and activation of the JAK2/STAT3 pathway. The dual benefits of PIM2 knockdown, suppressing inflammation while promoting bacterial clearance, positioned PIM2 as a potential therapeutic target for H. pylori-associated gastritis.