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Rv2647-Mediated NLRP3 Ubiquitination Inhibits Macrophage Pyroptosis and Promotes Mycobacterium tuberculosis Survival
Xiao Jin1, Haihao Yan1, Xiaolin Chen1
1Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China.
Abstract:
Inflammasome-mediated pyroptosis and cytokine release are crucial host defenses against intracellular pathogens. Mycobacterium tuberculosis (M. tb) is a successful intracellular pathogen, and it is largely unclear how it evades immune clearance and persists in macrophages. This study investigated whether the Rv2647 protein acts as a key virulence factor of M. tb and explored the potential mechanism of inhibiting macrophage pyroptosis and promoting M. tb survival. The results showed Rv2647 promoted NLRP3 degradation via enhancing its ubiquitination, which led to the inactivation of NLRP3/caspase-1/GSDMD and reduction of IL-1β secretion, thereby inhibiting macrophage pyroptosis and facilitating M. tb survival. Furthermore, Rv2647-mediated enhancement of NLRP3 ubiquitination and degradation depended on its binding to ISG15, competitively inhibiting ISGylation of NLRP3. The study identified Rv2647 as the key virulence factor that promoted M. tb survival by inhibiting macrophage pyroptosis, whose mechanism was to competitively inhibit the ISGylation of NLRP3 and enhance its ubiquitination, thus suppressing NLRP3/caspase-1/GSDMD-mediated pyroptosis. This finding highlighted Rv2647 as a promising drug target or vaccine antigen for tuberculosis prevention and control.
Insights
Mycobacterium tuberculosis uses Rv2647 protein to evade immune responses. This virulence factor inhibits macrophage pyroptosis by targeting NLRP3, promoting bacterial survival and suggesting new tuberculosis treatment strategies.
Area of Science:
- Immunology
- Microbiology
- Cellular Biology
Background:
- Inflammasome-mediated pyroptosis is essential for host defense against intracellular pathogens.
- Mycobacterium tuberculosis (M. tb) effectively evades immune clearance and persists within macrophages.
- The precise mechanisms by which M. tb evades host immunity remain incompletely understood.
Purpose of the Study:
- To investigate the role of the M. tb Rv2647 protein as a key virulence factor.
- To elucidate the mechanism by which Rv2647 inhibits macrophage pyroptosis and promotes M. tb survival.
Main Methods:
- Assessed the impact of Rv2647 on NLRP3 inflammasome activation and pyroptosis.
- Investigated the interaction between Rv2647, ISG15, and NLRP3 ubiquitination and degradation.
- Utilized cell-based assays to study M. tb survival in macrophages.
Main Results:
- Rv2647 promotes NLRP3 degradation by enhancing its ubiquitination, leading to pyroptosis inhibition.
- Rv2647 binds to ISG15, competitively inhibiting NLRP3 ISGylation and promoting its ubiquitination.
- Inhibition of the NLRP3/caspase-1/GSDMD pathway by Rv2647 facilitates M. tb survival within macrophages.
Conclusions:
- Rv2647 is a critical virulence factor for M. tb that suppresses host immune responses.
- Rv2647 inhibits macrophage pyroptosis by interfering with NLRP3 ISGylation and promoting ubiquitination.
- Rv2647 represents a potential therapeutic target for novel tuberculosis treatments and vaccines.
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