GRIM‐19 is a target of mycobacterial Zn2+ metalloprotease 1 and indispensable for NLRP3 inflammasome activation

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.