HCK regulates NLRP12-mediated PANoptosis

NOD-like receptors (NLRs) are a highly conserved family of cytosolic pattern recognition receptors that drive innate immune responses against pathogens, pathogen-associated molecular patterns, damage-associated molecular patterns, and homeostatic disruptions. Within the NLR family, NLRP12 was recently identified as a key regulator of PANoptosis, which is an innate immune, lytic cell death pathway initiated by innate immune sensors and driven by caspases and RIPKs through PANoptosome complexes. While NLRP12 activation is critical for maintaining homeostasis, aberrant activation has been implicated in a broad range of disorders, including cancers and metabolic, infectious, autoinflammatory, and hemolytic diseases. However, the molecular mechanisms of NLRP12 activation remain poorly understood. Here, we identified hematopoietic cell kinase (HCK) as a regulator of NLRP12-mediated PANoptosis. HCK expression was significantly upregulated in response to NLRP12-PANoptosome triggers. Moreover, <i>Hck</i> knockdown inhibited NLRP12-mediated PANoptosis. Computational analyses identified residues in the putative interaction interface between NLRP12 and HCK, suggesting that HCK likely binds NLRP12 in the region between its NACHT domain and pyrin domain (PYD); removal of the NLRP12 PYD abrogated this interaction in vitro. Overall, our work identifies HCK as a regulator of NLRP12-mediated PANoptosis, suggesting that it may serve as a potential therapeutic target for mitigating inflammation and pathology.