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Mycobacterium tuberculosis Limits Host Glycolysis and IL-1β by Restriction of PFK-M via MicroRNA-21.
Cell Reports ( IF 7.5 ) Pub Date : 2020-01-07 , DOI: 10.1016/j.celrep.2019.12.015 Emer E Hackett 1 , Hugo Charles-Messance 1 , Seónadh M O'Leary 2 , Laura E Gleeson 2 , Natalia Muñoz-Wolf 1 , Sarah Case 1 , Anna Wedderburn 1 , Daniel G W Johnston 1 , Michelle A Williams 3 , Alicia Smyth 4 , Mireille Ouimet 5 , Kathryn J Moore 5 , Ed C Lavelle 1 , Sinéad C Corr 3 , Stephen V Gordon 4 , Joseph Keane 2 , Frederick J Sheedy 6
Cell Reports ( IF 7.5 ) Pub Date : 2020-01-07 , DOI: 10.1016/j.celrep.2019.12.015 Emer E Hackett 1 , Hugo Charles-Messance 1 , Seónadh M O'Leary 2 , Laura E Gleeson 2 , Natalia Muñoz-Wolf 1 , Sarah Case 1 , Anna Wedderburn 1 , Daniel G W Johnston 1 , Michelle A Williams 3 , Alicia Smyth 4 , Mireille Ouimet 5 , Kathryn J Moore 5 , Ed C Lavelle 1 , Sinéad C Corr 3 , Stephen V Gordon 4 , Joseph Keane 2 , Frederick J Sheedy 6
Affiliation
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Increased glycolytic metabolism recently emerged as an essential process driving host defense against Mycobacterium tuberculosis (Mtb), but little is known about how this process is regulated during infection. Here, we observe repression of host glycolysis in Mtb-infected macrophages, which is dependent on sustained upregulation of anti-inflammatory microRNA-21 (miR-21) by proliferating mycobacteria. The dampening of glycolysis by miR-21 is mediated through targeting of phosphofructokinase muscle (PFK-M) isoform at the committed step of glycolysis, which facilitates bacterial growth by limiting pro-inflammatory mediators, chiefly interleukin-1β (IL-1β). Unlike other glycolytic genes, PFK-M expression and activity is repressed during Mtb infection through miR-21-mediated regulation, while other less-active isoenzymes dominate. Notably, interferon-γ (IFN-γ), which drives Mtb host defense, inhibits miR-21 expression, forcing an isoenzyme switch in the PFK complex, augmenting PFK-M expression and macrophage glycolysis. These findings place the targeting of PFK-M by miR-21 as a key node controlling macrophage immunometabolic function.
中文翻译：
结核分枝杆菌通过MicroRNA-21限制PFK-M限制宿主糖酵解和IL-1β。
近年来，糖酵解代谢的增加已成为驱动宿主防御结核分枝杆菌（Mtb）的必不可少的过程，但对该过程如何在感染过程中进行调节知之甚少。在这里，我们观察到感染Mtb的巨噬细胞中宿主糖酵解的抑制，这取决于通过分枝杆菌的增殖持续持续的抗炎microRNA-21（miR-21）的上调。miR-21对糖酵解的抑制作用是通过在糖酵解的确定阶段靶向磷酸果糖激酶肌肉（PFK-M）亚型来介导的，它通过限制促炎性介质（主要是白介素1β（IL-1β））促进细菌的生长。与其他糖酵解基因不同，在Mtb感染期间，通过miR-21介导的调节来抑制PFK-M的表达和活性，而其他活性较低的同工酶则占主导地位。值得注意的是 干扰素-γ（IFN-γ），驱动Mtb宿主防御，抑制miR-21表达，迫使PFK复合物中的同工酶转换，增加PFK-M表达和巨噬细胞糖酵解。这些发现将miR-21靶向PFK-M作为控制巨噬细胞免疫代谢功能的关键节点。
更新日期：2020-01-07
中文翻译：
结核分枝杆菌通过MicroRNA-21限制PFK-M限制宿主糖酵解和IL-1β。
近年来，糖酵解代谢的增加已成为驱动宿主防御结核分枝杆菌（Mtb）的必不可少的过程，但对该过程如何在感染过程中进行调节知之甚少。在这里，我们观察到感染Mtb的巨噬细胞中宿主糖酵解的抑制，这取决于通过分枝杆菌的增殖持续持续的抗炎microRNA-21（miR-21）的上调。miR-21对糖酵解的抑制作用是通过在糖酵解的确定阶段靶向磷酸果糖激酶肌肉（PFK-M）亚型来介导的，它通过限制促炎性介质（主要是白介素1β（IL-1β））促进细菌的生长。与其他糖酵解基因不同，在Mtb感染期间，通过miR-21介导的调节来抑制PFK-M的表达和活性，而其他活性较低的同工酶则占主导地位。值得注意的是 干扰素-γ（IFN-γ），驱动Mtb宿主防御，抑制miR-21表达，迫使PFK复合物中的同工酶转换，增加PFK-M表达和巨噬细胞糖酵解。这些发现将miR-21靶向PFK-M作为控制巨噬细胞免疫代谢功能的关键节点。
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