Rv2647-Mediated NLRP3 Ubiquitination Inhibits Macrophage Pyroptosis and Promotes Mycobacterium tuberculosis Survival.

IF 3.8 2区医学 Q2 CHEMISTRY, MEDICINAL

ACS Infectious Diseases Pub Date : 2025-10-01 DOI:10.1021/acsinfecdis.5c00192

Xiao Jin, Haihao Yan, Xiaolin Chen, Jiao Feng, Guoli Li, Jing Yao, Xingran Du, Ganzhu Feng

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引用次数: 0

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.

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rv2647介导的NLRP3泛素化抑制巨噬细胞热亡并促进结核分枝杆菌存活

炎性小体介导的焦亡和细胞因子释放是宿主对细胞内病原体的重要防御。结核分枝杆菌（M. tb）是一种成功的细胞内病原体，目前还不清楚它是如何逃避免疫清除并在巨噬细胞中持续存在的。本研究探讨Rv2647蛋白是否作为结核分枝杆菌的关键毒力因子，并探讨其抑制巨噬细胞热亡、促进结核分枝杆菌存活的潜在机制。结果表明，Rv2647通过增强NLRP3的泛素化，促进NLRP3的降解，导致NLRP3/caspase-1/GSDMD失活，IL-1β分泌减少，从而抑制巨噬细胞的焦亡，促进结核分枝杆菌的存活。此外，rv2647介导的NLRP3泛素化和降解的增强依赖于它与ISG15的结合，竞争性地抑制NLRP3的isg酰化。本研究发现Rv2647是通过抑制巨噬细胞热亡促进结核分枝杆菌存活的关键毒力因子，其机制是竞争性地抑制NLRP3的isg酰化，增强其泛素化，从而抑制NLRP3/caspase-1/ gsdmd介导的热亡。这一发现突出了Rv2647作为结核病预防和控制的一个有前景的药物靶点或疫苗抗原。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

期刊介绍： ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.