Mycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence
Mycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence
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DOI：
10.1073/pnas.2019305118
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发表时间：
2021-04-20
影响因子：
11.1
通讯作者：
Yang, Chen
中科院分区：
文献类型：
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作者：
Dong, Wenyue;Nie, Xiaoqun;Yang, Chen
宿主源性脂肪酸是致病性分枝杆菌感染过程中重要的碳源。然而，分枝杆菌细胞如何调节脂肪酸的分解代谢以服务于致病性尚不清楚。在这里，我们通过结合转录组学、染色质免疫沉淀和测序、基于c -13的动态通量分析、代谢组学和脂质组学，确定了一个ter家族转录因子FdmR是病原体海洋分枝杆菌中脂肪酸分解代谢的关键调节因子。在斑马鱼幼虫和成年斑马鱼中，FdmR缺陷的海洋分枝杆菌突变体严重减弱。突变体表现出生长缺陷，但对脂肪酸的底物消耗较高。FdmR被鉴定为参与脂肪酸降解和修饰的基因的长链酰基辅酶a （acyl-CoA）反应性抑制因子。我们证明了FdmR作为一个阀门的功能，引导外源脂肪酸从p氧化流向脂质生物合成，从而避免过度活跃的分解代谢和生物毒性中间体的积累。此外，我们发现FdmR抑制了通过I型脂肪酸合酶内源性合成的长链酰基辅酶a的降解。FdmR通过调节脂肪生成的长链酰基辅酶a的供应，控制毒力相关脂质和真菌酸酯的丰度和链长，并在细胞包膜的不渗透性中发挥重要作用。这些结果表明，尽管宿主来源的脂肪酸被用作重要的碳源，但脂肪酸过度活跃的分解代谢不利于分枝杆菌细胞的生长和致病性。因此，这项研究表明FdmR是一个潜在的有吸引力的化疗靶点。
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 C-13-based flux analysis, metabolomics, and lipidomics. An M. marinum mutant deficient in FdmR was severely attenuated in zebra-fish 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 p-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.