GRIM‐19 is a target of mycobacterial Zn2+ metalloprotease 1 and indispensable for NLRP3 inflammasome activation
GRIM‐19 is a target of mycobacterial Zn2+ metalloprotease 1 and indispensable for NLRP3 inflammasome activation
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DOI：
10.1096/fj.202101074rr
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发表时间：
2021-12
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通讯作者：
Tomomi Kurane;Tetsuro Matsunaga;T. Ida;K. Sawada;A. Nishimura;Masayuki Fukui;M. Umemura;M. Nakayama;N. Ohara;S. Matsumoto;T. Akaike;G. Matsuzaki;G. Takaesu
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作者：
Tomomi Kurane;Tetsuro Matsunaga;T. Ida;K. Sawada;A. Nishimura;Masayuki Fukui;M. Umemura;M. Nakayama;N. Ohara;S. Matsumoto;T. Akaike;G. Matsuzaki;G. Takaesu
结核病是一种由结核分枝杆菌引起的传染病，它主要感染巨噬细胞并建立细胞内寄生。已知分枝杆菌毒力因子Zn 2+金属蛋白酶1（Zmp 1）通过抑制半胱天冬酶-1从而导致吞噬体成熟停滞来抑制白细胞介素（IL）-1 β的产生。然而，Zmp 1抑制caspase-1的分子机制仍然是难以捉摸的。在这里，我们确定了GRIM-19（也称为NDUFA 13），线粒体呼吸链复合物I的一个重要亚基，作为一种新的Zmp 1结合蛋白。使用CRISPR/Cas9系统，我们产生了GRIM-19敲除的小鼠巨噬细胞系J774.1，并发现GRIM-19对于分枝杆菌感染期间的IL-1β产生以及响应NLRP 3炎性体激活刺激（如细胞外ATP或尼日利亚菌素）是必需的。我们还发现GRIM-19是线粒体活性氧和NLRP 3依赖的caspase-1活化所必需的。GRIM-19的缺失或Zmp 1的强制表达导致线粒体膜电位降低。我们的研究揭示了GRIM-19作为NLRP 3炎性小体的重要调节剂的先前未被认识的作用，以及分枝杆菌感染期间Zmp 1介导的IL-1β产生抑制的分子机制。
Tuberculosis is a communicable disease caused by Mycobacterium tuberculosis which primarily infects macrophages and establishes intracellular parasitism. A mycobacterial virulence factor Zn2+ metalloprotease 1 (Zmp1) is known to suppress interleukin (IL)‐1β production by inhibiting caspase‐1 resulting in phagosome maturation arrest. However, the molecular mechanism of caspase‐1 inhibition by Zmp1 is still elusive. Here, we identified GRIM‐19 (also known as NDUFA13), an essential subunit of mitochondrial respiratory chain complex I, as a novel Zmp1‐binding protein. Using the CRISPR/Cas9 system, we generated GRIM‐19 knockout murine macrophage cell line J774.1 and found that GRIM‐19 is essential for IL‐1β production during mycobacterial infection as well as in response to NLRP3 inflammasome‐activating stimuli such as extracellular ATP or nigericin. We also found that GRIM‐19 is required for the generation of mitochondrial reactive oxygen species and NLRP3‐dependent activation of caspase‐1. Loss of GRIM‐19 or forced expression of Zmp1 resulted in a decrease in mitochondrial membrane potential. Our study revealed a previously unrecognized role of GRIM‐19 as an essential regulator of NLRP3 inflammasome and a molecular mechanism underlying Zmp1‐mediated suppression of IL‐1β production during mycobacterial infection.