NLRP6 induces RIP1 kinase-dependent necroptosis via TAK1-mediated p38 MAPK /MK2 phosphorylation in S . typhimurium infection

• Published in: iScience 2024-04, Vol.27 (4), p.109339
• Main Authors: Deng, Qifeng, Yang, Sidi, Huang, Kai, Zhu, Yuan, Sun, Lanqing, Cao, Yu, Dong, Kedi, Li, Yuanyuan, Wu, Shuyan, Huang, Rui
• Format: Article
• Language: English
• ISSN: 2589-0042
• DOI: 10.1016/j.isci.2024.109339

Programmed cell death (PCD) is tightly orchestrated by molecularly defined executors and signaling pathways. NLRP6, a member of cytoplasmic pattern recognition receptors, has a multifaceted role in host resistance to bacterial infection. However, whether and how NLRP6 may contribute to regulate host PCD during Gram-negative bacterial infection remain to be illuminated. Here, we report that NLRP6 promotes RIP1 kinase-mediated necroptosis, a form of lytic PCD, in both an and model of infection. By downregulating TAK1-mediated p38 /MK2 phosphorylation, NLRP6 decreased RIP1 phosphorylation at residue S321 and subsequently increased RIP1 kinase-dependent MLKL phosphorylation. Suppression of p38 /MK2 cascade not only reduced the number of dead cells caused by NLRP6 but also decreased the systemic dissemination of . typhimurium resulting from NLRP6. Taken together, our findings provide new insights into the role and regulatory mechanism of NLRP6-associated antimicrobial responses by revealing a function for NLRP6 in regulating necroptosis.