Rv3371是一种三酰基甘油合成酶，它通过氧化还原稳态和丙酸解毒促进宿主结核分枝杆菌的存活

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis Pub Date : 2025-02-21 DOI:10.1016/j.tube.2025.102617

Rahul Kumar Maurya , Sarah Fatima , Swati Anand , Rajmani Raju , Suman Bharti , Shivangi Rastogi , Umamageswaran Venugopal , Amitava Sinha , Amit Singh , Manju Y. Krishnan

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引用次数: 0

摘要

三酰基甘油（TAG）是分枝杆菌的主要储存脂质。结核分枝杆菌（Mtb）基因组编码15种甘油三酯合成酶（Tgs），据推测，这些酶对底物的偏好不同，表明它们具有特定的生理作用。在这项研究中，我们研究了Tgs Rv3371在感染背景下的作用。Rv3371敲除（KO） Mtb在小鼠中减弱，巨噬细胞内相应的适应度较差。KO对游离长链脂肪酸更敏感，但对氧化和亚硝化的耐受性更强。酶动力学表明Rv3371对丙酰辅酶a有偏好。生长培养基中过量的丙酸比野生型和补充突变体更明显地延缓了KO的生长。这表明Rv3371在通过合成丙酰TAG降低Mtb中丙酸的毒性水平方面具有额外的作用。此外，甲基柠檬酸循环的化学抑制导致KO中甲基支化脂质的减少。总的来说，结果表明Rv3371通过其TAG存储之外的作用在宿主的Mtb存活中发挥作用。

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Rv3371, a triacylglycerol synthase promotes survival of Mycobacterium tuberculosis in the host through its contributions to redox homeostasis and propionate detoxification

Triacylglycerol (TAG) is the major storage lipid of mycobacteria. Mycobacterium tuberculosis (Mtb) genome encodes 15 triacylglycerol synthases (Tgs), which are speculated to differ in substrate preference, suggesting specific physiological roles. In this study, we investigated the role of a Tgs, Rv3371, in the context of infection. Rv3371 knock-out (KO) Mtb was attenuated in mice, with corresponding poor fitness inside macrophages. The KO was more sensitive to free long-chain fatty acids, but was more tolerant to oxidative and nitrosative stresses. Enzyme kinetics of Rv3371 showed its preference for propionyl-CoA. Excess propionate in growth medium retarded the growth of the KO more significantly than the wild type and complemented mutant. This suggests an additional role of Rv3371 in reducing toxic levels of propionate in Mtb by synthesising propionyl TAG. Moreover, chemical inhibition of methylcitrate cycle caused a decrease in methyl-branched lipids in the KO. Overall, the results suggest a role of Rv3371 in Mtb survival in the host through its roles beyond TAG storage.

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来源期刊

Tuberculosis 医学-呼吸系统

CiteScore

4.60

自引率

3.10%

发文量

审稿时长

49 days

期刊介绍： Tuberculosis is a speciality journal focusing on basic experimental research on tuberculosis, notably on bacteriological, immunological and pathogenesis aspects of the disease. The journal publishes original research and reviews on the host response and immunology of tuberculosis and the molecular biology, genetics and physiology of the organism, however discourages submissions with a meta-analytical focus (for example, articles based on searches of published articles in public electronic databases, especially where there is lack of evidence of the personal involvement of authors in the generation of such material). We do not publish Clinical Case-Studies. Areas on which submissions are welcomed include: -Clinical TrialsDiagnostics- Antimicrobial resistance- Immunology- Leprosy- Microbiology, including microbial physiology- Molecular epidemiology- Non-tuberculous Mycobacteria- Pathogenesis- Pathology- Vaccine development. This Journal does not accept case-reports. The resurgence of interest in tuberculosis has accelerated the pace of relevant research and Tuberculosis has grown with it, as the only journal dedicated to experimental biomedical research in tuberculosis.