LAUSR

As a key virulence factor for persistent colonization, Urease B subunit (UreB) is considered to be an ideal vaccine antigen against Helicobacter pylori (H. pylori) infection. However, the role and molecular mechanisms of UreB involved in immune microenvironment dysregulation still remains largely unknown. In the present study, we evaluated the effects of UreB on macrophage activation and found that UreB induced PD-L1 accumulation on Bone marrow-derived macrophages (BMDMs). Co-culture assays further revealed that UreB-induced PD-L1 expression on BMDMs significantly decreased the proliferation and secretion of cytolytic molecules (granzyme B and perforin) of splenic CD8 + T cells isolated from inactivated H. pylori-immunized mice. More importantly, myosin heavy chain 9 (Myh9) was confirmed to be a direct membrane receptor of UreB via using LC-MS/MS and Co-immunoprecipitation and required for PD-L1 upregulation on BMDMs. Molecular studies further demonstrated that the interaction between UreB and Myh9 decreased GCN2 autophosphorylation and enhanced intracellular pool of amino acids, leading to the upregulation of S6K phosphorylation, a commonly used marker for monitoring activation of mTORC1 signaling activity. Furthermore, blocking mTORC1 activation with its inhibitor Temsirolimus reversed UreB-induced PD-L1 upregulation and the subsequently inhibitory effects of BMDMs on activation of cytotoxic CD8 + T cell responses. Overall, our data unveil a novel immunosuppressive mechanism of UreB during H. pylori infection, which may provide valuable clue for the optimization of H. pylori vaccine.