NLRC4, also known as NLR-family CARD-containing protein 4, is a key component of the inflammasome, a cytosolic multiprotein complex. Inflammasomes sense microbial infections or host cell damage, triggering cytokine production and pyroptosis, a pro-inflammatory form of cell death. The NLRC4 inflammasome is crucial for restricting bacterial infections and is involved in various immune-related pathways [2,3,4,5]. Genetic models, such as KO mouse models, have been instrumental in studying its functions.

SIRT3-deficient KO models showed that SIRT3-mediated deacetylation of NLRC4 is pivotal for NLRC4 inflammasome activation and pyroptosis both in vitro and in vivo. SIRT3 promotes NLRC4 inflammasome assembly by inducing more ASC speck formation and ASC oligomerization [1]. In addition, NLRC4-deficient mice showed attenuated Ifn-β, Isg54, and Isg56 mRNA transcription, TBK1 phosphorylation, and augmented viral replications upon herpes simplex virus-1 (HSV-1) infection, indicating that NLRC4 promotes the cGAS-STING signaling pathway [6].

In conclusion, NLRC4 plays essential roles in immunity and inflammation, mainly through its involvement in inflammasome activation and regulation of related signaling pathways. The use of KO mouse models has revealed its significance in bacterial infections, auto-inflammatory diseases, and antiviral innate immunity, providing insights into the underlying mechanisms of these biological processes and potential therapeutic targets.