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标题：MadR mediates acyl CoA-dependent regulation of mycolic acid desaturation in mycobacteria
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作者：Charlotte Cooper ; Eliza J. R. Peterson ; Rebeca Bailo 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：8
DOI：10.1073/pnas.2111059119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance 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 C 16 to C 24, 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.
关键词：enMycobacteriumtuberculosismycolic acidTetR regulatorcell envelope