MadR mediates acyl CoA-dependent regulation of mycolic acid desaturation in mycobacteria.
MadR mediates acyl CoA-dependent regulation of mycolic acid desaturation in mycobacteria.
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DOI：
10.1073/pnas.2111059119
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发表时间：
2022-02-22
影响因子：
11.1
通讯作者：
Bhatt A
中科院分区：
文献类型：
--
作者：
Cooper C;Peterson EJR;Bailo R;Pan M;Singh A;Moynihan P;Nakaya M;Fujiwara N;Baliga N;Bhatt A
我们的研究表明，mycolic acid desaturase regulator （MadR）作为一个分子开关，控制分枝杆菌胞膜关键脂质mycolic acid的去饱和和生物合成。MadR通过一种独特的机制起作用，其中它结合各种酰基辅酶a（酰基辅酶a），但只有饱和的酰基辅酶a才能缓解DNA的结合和抑制。这表明了一种独特的机制，涉及到酰基辅酶a池的感知，作为协调霉菌酸重塑和生物合成的检查点，以响应细胞表面扰动。我们的研究结果进一步加深了我们对分枝杆菌如何控制细胞壁组成以应对各种环境（从土壤到感染巨噬细胞的细胞内生态位）的应激的理解，这对理解结核杆菌的发病机制策略具有重要意义。结核分枝杆菌具有富含脂质的细胞包膜，在整个感染过程中被重塑以使宿主能够适应。很少有转录调节因子被表征为协调分枝杆菌细胞壁脂质分枝杆菌酸的合成。在这里，我们发现霉菌酸去饱和酶调节剂（MadR）是霉菌酸去饱和酶基因desA1和desA2的转录抑制因子，在细胞包膜胁迫下控制霉菌酸的去饱和和生物合成。一种无madr的耻毛分枝杆菌突变体表现出细胞壁受损、外菌膜改变、不饱和α-真菌酸积累、抗细菌药物敏感性和细胞表面破坏等特征。转录组学分析显示，madR缺失后显著下调的脂质代谢基因包括酰基辅酶A （acyl- coa）脱氢酶，暗示其间接控制β-氧化途径。电迁移性转移分析和结合亲和力表明，MadR具有独特的酰基辅酶a池感应机制，可以结合一系列酰基辅酶a，包括具有不饱和和饱和酰基链的酰基辅酶a。与链长为C16 ~ C24的饱和酰基辅酶a结合时，desA1/desA2的MadR抑制得到缓解，而与短链和不饱和酰基辅酶a结合时则没有影响。我们提出这种调节机制与其他霉菌酸和脂肪酸合成调节机制不同，并将MadR作为关键的调节检查点，在宿主源性细胞表面扰动的感染过程中协调霉菌酸重塑。
Our studies show that the mycolic acid desaturase regulator (MadR) acts as a molecular switch, controlling the desaturation and biosynthesis of mycolic acids, key lipids of the cell envelopes of mycobacteria. MadR works by a distinct mechanism wherein it binds various acyl-coenzyme As (aceyl-CoAs), but only saturated acyl-CoAs relieve DNA binding and repression. This suggests a unique mechanism that involves sensing of acyl-CoA pools as a checkpoint for coordinating mycolic acid remodeling and biosynthesis in response to cell surface perturbation. Our findings further our understanding of how mycobacteria control cell wall composition in response to stress across various environments ranging from soil to an intracellular niche in infected macrophages, with implications for understanding strategies for pathogenesis in the tubercle bacillus. Mycobacterium tuberculosis has a lipid-rich cell envelope that is remodeled throughout infection to enable adaptation within the host. Few transcriptional regulators have been characterized that coordinate synthesis of mycolic acids, the major cell wall lipids of mycobacteria. Here, we show that the mycolic acid desaturase regulator (MadR), a transcriptional repressor of the mycolate desaturase genes desA1 and desA2, controls mycolic acid desaturation and biosynthesis in response to cell envelope stress. A madR-null mutant of M. smegmatis exhibited traits of an impaired cell wall with an altered outer mycomembrane, accumulation of a desaturated α-mycolate, susceptibility to antimycobacterials, and cell surface disruption. Transcriptomic profiling showed that enriched lipid metabolism genes that were significantly down-regulated upon madR deletion included acyl-coenzyme A (aceyl-CoA) dehydrogenases, implicating it in the indirect control of β-oxidation pathways. Electromobility shift assays and binding affinities suggest a unique acyl-CoA pool–sensing mechanism, whereby MadR is able to bind a range of acyl-CoAs, including those with unsaturated as well as saturated acyl chains. MadR repression of desA1/desA2 is relieved upon binding of saturated acyl-CoAs of chain length C16 to C24, while no impact is observed upon binding of shorter chain and unsaturated acyl-CoAs. We propose this mechanism of regulation as distinct to other mycolic acid and fatty acid synthesis regulators and place MadR as the key regulatory checkpoint that coordinates mycolic acid remodeling during infection in response to host-derived cell surface perturbation.
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影响因子：
4.8
作者：
Man, DeDe Kwun-Wai;Kanno, Tokuwa;Mason, A. James
通讯作者：
Mason, A. James
分枝菌酸：破译并瞄准结核杆菌的致命弱点。
影响因子：
3.6
作者：
Nataraj V;Varela C;Javid A;Singh A;Besra GS;Bhatt A
通讯作者：
Bhatt A
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
DOI：
10.1093/bioinformatics/bts251
发表时间：
2012-07-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Jiao X;Sherman BT;Huang da W;Stephens R;Baseler MW;Lane HC;Lempicki RA
通讯作者：
Lempicki RA
影响因子：
4.6
作者：
Li Q;Xie L;Long Q;Mao J;Li H;Zhou M;Xie J
通讯作者：
Xie J