气候变化领域集成服务门户(CCPortal): Mycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence

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DOI	10.1073/pnas.2019305118
	Mycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence
	Dong W.; Nie X.; Zhu H.; Liu Q.; Shi K.; You L.; Zhang Y.; Fan H.; Yan B.; Niu C.; Lyu L.-D.; Zhao G.-P.; Yang C.
发表日期	2021
ISSN	00278424
卷号	118 期号:16
英文摘要	Host-derived fatty acids are an important carbon source for pathogenic mycobacteria during infection. How mycobacterial cells regulate the catabolism of fatty acids to serve the pathogenicity, however, remains unknown. Here, we identified a TetR-family transcriptional factor, FdmR, as the key regulator of fatty acid catabolism in the pathogen Mycobacterium marinum by combining use of transcriptomics, chromatin immunoprecipitation followed by sequencing, dynamic 13C-based flux analysis, metabolomics, and lipidomics. An M. marinum mutant deficient in FdmR was severely attenuated in zebrafish larvae and adult zebrafish. The mutant showed defective growth but high substrate consumption on fatty acids. FdmR was identified as a long-chain acyl-coenzyme A (acyl-CoA)-responsive repressor of genes involved in fatty acid degradation and modification. We demonstrated that FdmR functions as a valve to direct the flux of exogenously derived fatty acids away from β-oxidation toward lipid biosynthesis, thereby avoiding the overactive catabolism and accumulation of biologically toxic intermediates. Moreover, we found that FdmR suppresses degradation of long-chain acyl-CoAs endogenously synthesized through the type I fatty acid synthase. By modulating the supply of long-chain acyl-CoAs for lipogenesis, FdmR controls the abundance and chain length of virulence-associated lipids and mycolates and plays an important role in the impermeability of the cell envelope. These results reveal that despite the fact that host-derived fatty acids are used as an important carbon source, overactive catabolism of fatty acids is detrimental to mycobacterial cell growth and pathogenicity. This study thus presents FdmR as a potentially attractive target for chemotherapy. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Fatty acid; Lipid homeostasis; Metabolic regulation; Mycobacterium
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179796
作者单位	CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences (CAS), Shanghai, 200032, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, United States; Key Laboratory of Medical Molecular Virology, The Ministry of Education, National Health Commission, Chinese Academy of Medical Sciences (MOE/NHC/CAMS), School of Basic Medical Sciences, Department of Microbiology, School of Life Sciences, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200000, China; Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200032, China
推荐引用方式 GB/T 7714	Dong W.,Nie X.,Zhu H.,et al. Mycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence[J],2021,118(16).
APA	Dong W..,Nie X..,Zhu H..,Liu Q..,Shi K..,...&Yang C..(2021).Mycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence.Proceedings of the National Academy of Sciences of the United States of America,118(16).
MLA	Dong W.,et al."Mycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence".Proceedings of the National Academy of Sciences of the United States of America 118.16(2021).