<i>Helicobacter pylori</i> CagA Interacts with SHP-1 to Suppress the Immune Response by Targeting TRAF6 for K63-Linked Ubiquitination

Abstract

<i>Helicobacter pylori</i> is the major etiological agent for most gastric cancer. CagA has been reported to be an important virulence factor of <i>H. pylori</i>, but its effect on the immune response is not yet clear. In this study, wild-type C57BL/6 mice and Ptpn6^me-v/me-v mice were randomly assigned for infection with <i>H. pylori</i> We demonstrated that CagA suppressed <i>H. pylori</i>-stimulated expression of proinflammatory cytokines in vivo. Besides, we infected mouse peritoneal macrophages RAW264.7 and AGS with <i>H. pylori</i> Our results showed that CagA suppressed expression of proinflammatory cytokines through inhibiting the MAPKs and NF-κB pathways activation in vitro. Mechanistically, we found that CagA interacted with the host cellular tyrosine phosphatase SHP-1, which facilitated the recruitment of SHP-1 to TRAF6 and inhibited the K63-linked ubiquitination of TRAF6, which obstructed the transmission of signal downstream. Taken together, these findings reveal a previously unknown mechanism by which CagA negatively regulates the posttranslational modification of TRAF6 in innate antibacterial immune response and provide molecular basis for new therapeutics to treat microbial infection.