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GRIM‐19 is a target of mycobacterial Zn 2+ metalloprotease 1 and indispensable for NLRP3 inflammasome activation
Author(s) -
Kurane Tomomi,
Matsunaga Tetsuro,
Ida Tomoaki,
Sawada Kazuko,
Nishimura Akira,
Fukui Masayuki,
Umemura Masayuki,
Nakayama Masaaki,
Ohara Naoya,
Matsumoto Sohkichi,
Akaike Takaaki,
Matsuzaki Goro,
Takaesu Giichi
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202101074rr
Subject(s) - inflammasome , caspase 1 , biology , intracellular , microbiology and biotechnology , virulence factor , virulence , inflammation , immunology , biochemistry , gene
Tuberculosis is a communicable disease caused by Mycobacterium tuberculosis which primarily infects macrophages and establishes intracellular parasitism. A mycobacterial virulence factor Zn 2+ 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.