Mycobacterium tuberculosis infection up-regulates MFN2 expression to promote NLRP3 inflammasome formation.
Mycobacterium tuberculosis infection up-regulates MFN2 expression to promote NLRP3 inflammasome formation.
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DOI：
10.1074/jbc.ra120.014077
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发表时间：
2020-12-18
期刊：
影响因子：
--
通讯作者：
Li W
中科院分区：
文献类型：
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作者：
Xu F;Qi H;Li J;Sun L;Gong J;Chen Y;Shen A;Li W
由结核分枝杆菌（MTB）感染引起的结核病（TB）是全世界，特别是儿童死亡的主要原因之一。然而，MTB感染其细胞宿主、激活免疫反应并引发炎症的机制尚不清楚。线粒体在具有pyrin结构域3的核苷酸结合寡聚化结构域样受体（NLRP3）炎症小体的起始和激活中起重要作用，其中线粒体相关内质网膜（MAMs）可能作为炎症小体组装和激活的平台。此外，有丝分裂蛋白2 （MFN2）与MAMs的形成有关，但线粒体和MFN2在MTB感染中的作用尚未阐明。通过对结核病患者的微细胞分析和体外MTB刺激巨噬细胞，我们观察到活动性结核病患者外周血单个核细胞中MFN2的上调。此外，我们发现MTB特异性抗原ESAT-6或MTB裂解物刺激MTB可促进MFN2与NLRP3炎症小体的相互作用，导致炎症小体的组装和激活，随后导致IL-1β的分泌。这些发现表明MFN2和线粒体在MTB感染过程中病原体-宿主相互作用中起重要作用。
Tuberculosis (TB), caused by the infection of Mycobacterium tuberculosis (MTB), is one of the leading causes of death worldwide, especially in children. However, the mechanisms by which MTB infects its cellular host, activates an immune response, and triggers inflammation remain unknown. Mitochondria play important roles in the initiation and activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome, where mitochondria-associated endoplasmic reticulum membranes (MAMs) may serve as the platform for inflammasome assembly and activation. Additionally, mitofusin 2 (MFN2) is implicated in the formation of MAMs, but, the roles of mitochondria and MFN2 in MTB infection have not been elucidated. Using mircroarry profiling of TB patients and in vitro MTB stimulation of macrophages, we observed an up-regulation of MFN2 in the peripheral blood mononuclear cells of active TB patients. Furthermore, we found that MTB stimulation by MTB-specific antigen ESAT-6 or lysate of MTB promoted MFN2 interaction with NLRP3 inflammasomes, resulting in the assembly and activation of the inflammasome and, subsequently, IL-1β secretion. These findings suggest that MFN2 and mitochondria play important role in the pathogen-host interaction during MTB infection.