Serine protease Rv2569c inhibits inflammatory response and promotes intracellular survival of Mycobacterium tuberculosis by targeting the RhoG-NF-κB-NLRP3 pathway

Innate immunity is dominant in protecting the host's defense against intracellular Bacterial infections. The secretion of IL-1β and activation of NLRP3 inflammasome in macrophages play a critical role in combating Mycobacterium tuberculosis (M.tb) infections. M.tb is an extremely successful intracellular pathogen that evades host innate immunity by interfering with a wide range of macrophage functions. However, the precise Infection mechanism remains unclear. This study demonstrates that the mycobacterial serine protease Rv2569c interacts with RhoG in macrophages, effectively blocking the NF-κB signaling pathway's initiation and suppressing NLRP3 inflammasome activation, ultimately leading to a decrease in IL-1β secretion and promoting mycobacterial survival within macrophages. To investigate the role of Rv2569c in M.tb Infection, an Rv2569c-deficient strain (H37RvΔRv2569c) was used to demonstrate a weakened suppression of the inflammatory response and lower intracellular survival compared to the wild-type (H37Rv) and complemented strain (H37RvΔRv2569c + Rv2569c) through in vitro and in vivo experiments. The findings provide the first proof that RhoG serves as an endogenous host sensor for pathogens and that Rv2569c-RhoG-mediated inflammatory response plays a crucial role in mycobacterial immune evasion.