Mycobacterium tuberculosis induces the miR-33 locus to reprogram autophagy and host lipid metabolism.
Mycobacterium tuberculosis induces the miR-33 locus to reprogram autophagy and host lipid metabolism.
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DOI：
10.1038/ni.3434
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发表时间：
2016-06
影响因子：
30.5
通讯作者：
Moore KJ
中科院分区：
文献类型：
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作者：
Ouimet M;Koster S;Sakowski E;Ramkhelawon B;van Solingen C;Oldebeken S;Karunakaran D;Portal-Celhay C;Sheedy FJ;Ray TD;Cecchini K;Zamore PD;Rayner KJ;Marcel YL;Philips JA;Moore KJ
结核分枝杆菌（Mtb）通过逃避递送至溶酶体并促进脂质体的积累而在巨噬细胞内存活，脂质体充当细菌营养源。在这里，我们表明，通过诱导miR-33及其乘客链miR-33*，Mtb抑制参与自噬，溶酶体功能和脂肪酸氧化的整合途径，以支持细菌复制。通过遗传或药理学手段沉默miR-33和miR-33* 通过关键自噬效应物如ATG 5、ATG 12、LC 3B和LAMP 1的去抑制以及转录因子FOXO 3和TFEB的AMPK依赖性激活促进自噬通量，增强脂质催化剂和Mtb异噬。这些数据定义了Mtb利用的哺乳动物miRNA回路，以协调抑制自噬并重新编程宿主脂质代谢，以使宿主细胞内存活和持久。
Mycobacterium tuberculosis (Mtb) survives within macrophages by evading delivery to the lysosome and promoting the accumulation of lipid bodies, which serve as a bacterial source of nutrients. Here we show that by inducing miR-33 and its passenger strand miR-33*, Mtb inhibits integrated pathways involved in autophagy, lysosomal function and fatty acid oxidation to support bacterial replication. Silencing of miR-33 and miR-33* by genetic or pharmacological means promotes autophagy flux through derepression of key autophagy effectors such as ATG5, ATG12, LC3B and LAMP1 and AMPK-dependent activation of the transcription factors FOXO3 and TFEB, enhancing lipid catabolism and Mtb xenophagy. These data define a mammalian miRNA circuit utilized by Mtb to coordinately inhibit autophagy and reprogram host lipid metabolism to enable intracellular survival and persistence in the host.