NLRP6 induces RIP1 kinase-dependent necroptosis via TAK1-mediated p38MAPK/MK2 phosphorylation in S. Typhimurium infection

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 in vitro and in vivo model of S. Typhimurium infection. By downregulating TAK1-mediated p38MAPK/MK2 phosphorylation, NLRP6 decreased RIP1 phosphorylation at residue S321 and subsequently increased RIP1 kinase-dependent MLKL phosphorylation. Suppression of p38MAPK/MK2 cascade not only reduced the number of dead cells caused by NLRP6 but also decreased the systemic dissemination of S. 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.