Coupling of Peptidoglycan Synthesis to Central Metabolism in Mycobacteria: Post-transcriptional Control of CwlM by Aconitase.
Coupling of Peptidoglycan Synthesis to Central Metabolism in Mycobacteria: Post-transcriptional Control of CwlM by Aconitase.
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DOI：
10.1016/j.celrep.2020.108209
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发表时间：
2020-09-29
期刊：
影响因子：
8.8
通讯作者：
Green J
中科院分区：
文献类型：
--
作者：
Bancroft PJ;Turapov O;Jagatia H;Arnvig KB;Mukamolova GV;Green J
结核分枝杆菌导致人类结核病，需要更好地了解其生物学，以确定可能在开发新疗法中利用的漏洞。结核分枝杆菌核心代谢酶乌头酸酶（AcnA）的铁硫簇在暴露于氧化/亚硝化应激或铁螯合剂时解体。无催化活性的apo-AcnA与类似于位于另一种必需蛋白质CwlM（肽聚糖合成的调节剂）的转录物内的铁响应元件（IRE）的序列相互作用。用具有破坏的IRE的结核分枝杆菌cwlM补充的耻垢分枝杆菌cwlM条件突变体不能从氧化、亚硝化和铁饥饿应激的组合中恢复。用缺乏功能性IRE的cwIM基因补充的等同结核分枝杆菌cwIM条件突变体在THP-1巨噬细胞中表现出生长缺陷。AcnA似乎起偶联肽聚糖合成和中枢代谢的作用，这种偶联的破坏可能使分枝杆菌容易受到巨噬细胞的攻击。结核分枝杆菌cwlM IRE的突变损害脱辅基乌头酸酶的结合脱辅基乌头酸酶：cwlM IRE相互作用偶联代谢和肽聚糖合成通过cwlM IRE的突变使耻垢分枝杆菌对宿主相关的应激敏感性解耦结核分枝杆菌中cwlM IRE的突变导致巨噬细胞的生长缺陷班克罗夫特et al.表明宿主相关应激引起结核分枝杆菌顺乌头酸酶铁-硫簇的分解。所得脱辅基乌头酸酶结合cwlM转录物内的IRE样序列。这种相互作用的破坏增强了分枝杆菌对铁饥饿、亚硝化和氧化应激的敏感性，并损害了巨噬细胞的生长。
Mycobacterium tuberculosis causes human tuberculosis, and a better understanding of its biology is required to identify vulnerabilities that might be exploited in developing new therapeutics. The iron-sulfur cluster of the essential M. tuberculosis central metabolic enzyme, aconitase (AcnA), disassembles when exposed to oxidative/nitrosative stress or iron chelators. The catalytically inactive apo-AcnA interacts with a sequence resembling an iron-responsive element (IRE) located within the transcript of another essential protein, CwlM, a regulator of peptidoglycan synthesis. A Mycobacterium smegmatis cwlM conditional mutant complemented with M. tuberculosis cwlM with a disrupted IRE is unable to recover from combinations of oxidative, nitrosative, and iron starvation stresses. An equivalent M. tuberculosis cwlM conditional mutant complemented with the cwlM gene lacking a functional IRE exhibits a growth defect in THP-1 macrophages. It appears that AcnA acts to couple peptidoglycan synthesis and central metabolism, and disruption of this coupling potentially leaves mycobacteria vulnerable to attack by macrophages. Mutation of the M. tuberculosis cwlM IRE impairs binding by apo-aconitase Apo-aconitase:cwlM IRE interactions couple metabolism and peptidoglycan synthesis Decoupling by mutation of the cwlM IRE sensitizes M. smegmatis to host-related stresses Mutation of the cwlM IRE in M. tuberculosis results in a growth defect in macrophages Bancroft et al. show that host-associated stresses cause disassembly of the iron-sulfur cluster of Mycobacterium tuberculosis aconitase. The resulting apo-aconitase binds an IRE-like sequence within the cwlM transcript. Disruption of this interaction enhances the sensitivity of mycobacteria to iron starvation and nitrosative and oxidative stresses and impairs growth in macrophages.
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DOI：
10.1038/s41579-018-0013-4
发表时间：
2018-08
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
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通讯作者：
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DOI：
10.1099/00221287-142-4-915
发表时间：
1996-04-01
期刊：
MICROBIOLOGY-UK
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Sharp, PM
影响因子：
6.4
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10.1073/pnas.96.18.10412
发表时间：
1999-08-31
影响因子：
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通讯作者：
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