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

doi:10.1016/j.isci.2024.109339

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

iScience. 2024 Feb 28;27(4):109339. doi: 10.1016/j.isci.2024.109339. eCollection 2024 Apr 19.

Authors

Qifeng Deng^{1

2}, Sidi Yang³, Kai Huang⁴, Yuan Zhu^{1

5}, Lanqing Sun^{1

6}, Yu Cao¹, Kedi Dong^{1

7}, Yuanyuan Li⁸, Shuyan Wu¹, Rui Huang¹

Affiliations

¹ 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.
² 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.
³ Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510005, P.R. China.
⁴ Orthopaedic Institute, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu 214062, P.R. China.
⁵ Department of Laboratory Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, P.R. China.
⁶ Department of Laboratory Medicine, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214000, P.R. China.
⁷ Department of Blood Transfusion, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, P.R. China.
⁸ Experimental Center, Suzhou Medical College of Soochow University, No. 199, Ren Ai Road, Suzhou, Jiangsu 215123, P.R. China.

Abstract

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 p38^MAPK/MK2 phosphorylation, NLRP6 decreased RIP1 phosphorylation at residue S321 and subsequently increased RIP1 kinase-dependent MLKL phosphorylation. Suppression of p38^MAPK/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.

Keywords: Cell biology; Microbiology; Molecular microbiology.