NLRP6 induces RIP1 kinase-dependent necroptosis via TAK1-mediated p38MAPK/MK2 phosphorylation in S. typhimurium infection
Qifeng Deng,
Sidi Yang,
Kai Huang,
Yuan Zhu,
Lanqing Sun,
Yu Cao,
Kedi Dong,
Yuanyuan Li,
Shuyan Wu,
Rui Huang
Affiliations
Qifeng Deng
Department of Medical Microbiology, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Key Laboratory of Pathogen Bioscience and Anti-infective Medicine, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China; MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, P.R. China
Sidi Yang
Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510005, P.R. China
Kai Huang
Orthopaedic Institute, Wuxi 9th People’s Hospital Affiliated to Soochow University, Wuxi, Jiangsu 214062, P.R. China
Yuan Zhu
Department of Medical Microbiology, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Key Laboratory of Pathogen Bioscience and Anti-infective Medicine, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China; Department of Laboratory Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, P.R. China
Lanqing Sun
Department of Medical Microbiology, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Key Laboratory of Pathogen Bioscience and Anti-infective Medicine, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China; Department of Laboratory Medicine, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214000, P.R. China
Yu Cao
Department of Medical Microbiology, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Key Laboratory of Pathogen Bioscience and Anti-infective Medicine, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
Kedi Dong
Department of Medical Microbiology, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Key Laboratory of Pathogen Bioscience and Anti-infective Medicine, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China; Department of Blood Transfusion, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, P.R. China
Yuanyuan Li
Experimental Center, Suzhou Medical College of Soochow University, No. 199, Ren Ai Road, Suzhou, Jiangsu 215123, P.R. China; Corresponding author
Shuyan Wu
Department of Medical Microbiology, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Key Laboratory of Pathogen Bioscience and Anti-infective Medicine, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China; Corresponding author
Rui Huang
Department of Medical Microbiology, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Key Laboratory of Pathogen Bioscience and Anti-infective Medicine, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China; Corresponding author
Summary: 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 Salmonella 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.
