Nadendla Eswar Kumar, Alluri Priyanshu, Sundaram Balamurugan, Kumar Sivakumar Prasanth, Chadchan Sangappa B, Sarkar Roman, Kanneganti Thirumala-Devi
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Proc Natl Acad Sci U S A. 2025 May 27;122(21):e2422079122. doi: 10.1073/pnas.2422079122. Epub 2025 May 23.
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, 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.
NOD样受体（NLRs）是一类高度保守的胞质模式识别受体家族，可驱动针对病原体、病原体相关分子模式、损伤相关分子模式和体内稳态破坏的先天免疫反应。在NLR家族中，NLRP12最近被确定为PAN细胞焦亡的关键调节因子，PAN细胞焦亡是一种由先天免疫传感器启动、由半胱天冬酶和RIPKs通过PAN细胞焦亡体复合物驱动的先天免疫溶解性细胞死亡途径。虽然NLRP12的激活对于维持体内稳态至关重要，但异常激活与多种疾病有关，包括癌症、代谢性疾病、感染性疾病、自身炎症性疾病和溶血性疾病。然而，NLRP12激活的分子机制仍知之甚少。在这里，我们确定造血细胞激酶（HCK）是NLRP12介导的PAN细胞焦亡的调节因子。HCK的表达在对NLRP12 - PAN细胞焦亡体触发因子的反应中显著上调。此外，敲低HCK可抑制NLRP12介导的PAN细胞焦亡。计算分析确定了NLRP12与HCK之间假定相互作用界面中的残基，这表明HCK可能在其NACHT结构域和吡啉结构域（PYD）之间的区域结合NLRP12；去除NLRP12的PYD可在体外消除这种相互作用。总体而言，我们的工作确定HCK是NLRP12介导的PAN细胞焦亡的调节因子，表明它可能作为减轻炎症和病理的潜在治疗靶点。
