M. tb Rv0927c suppresses the activation of HIF-1α pathway through VHL-mediated ubiquitination and NF-κB/COX-2 pathway to enhance mycobacteria survival

Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, employs various effector proteins to target and modulate host defenses. Our previous study showed that M. tuberculosis protein Rv0927c can promote the survival of intracellular mycobacteria, but the underlying mechanisms remain poorly understood. Here, we found that Rv0927c inhibited Mycobacterium smegmatis (M. smegmatis) induced hypoxia-inducible factor-1α (HIF-1α) activation in macrophages, and HIF-1α is required for Rv0927c to promote mycobacteria survival. Western blot analysis showed that Rv0927c promoted the proteasomal degradation of HIF-1α via Von Hippel-Lindau (VHL)-mediated ubiquitination and inhibited the nuclear localization of HIF-1α through the NF-κB/COX-2 pathway, thereby suppressing HIF-1α pathway activation. Furthermore, Rv0927c suppressed the host glycolytic metabolism, which is known to be regulated by HIF-1α and depended on the glycolysis process to promote mycobacterial survival. Our findings provide evidence that Rv0927c inhibits the activation of HIF-1α pathway, allowing pathogens to evade host immune responses, suggesting that targeting Rv0927c or HIF-1α might be a potential anti-tuberculosis therapy.