1. Academic Validation
  2. Salmonella pSLT-encoded effector SpvB promotes RIPK3-dependent necroptosis in intestinal epithelial cells

Salmonella pSLT-encoded effector SpvB promotes RIPK3-dependent necroptosis in intestinal epithelial cells

  • Cell Death Discov. 2022 Feb 2;8(1):44. doi: 10.1038/s41420-022-00841-9.
Kedi Dong  # 1 Yuan Zhu  # 1 Qifeng Deng 1 Lanqing Sun 1 Sidi Yang 2 Kai Huang 3 Yu Cao 1 Yuanyuan Li 1 Shuyan Wu 4 Rui Huang 5
Affiliations

Affiliations

  • 1 Department of Medical Microbiology, School of Biology & Basic Medical Sciences, Medical College of Soochow University, No. 199, Ren Ai Road, Suzhou, Jiangsu, 215123, P. R. China.
  • 2 Centre for Infection and Immunity Studies (CIIS), School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, 518107, P. R. China.
  • 3 Cambridge-Suda Genomic Resource Center, Jiangsu Key Laboratory of Neuropsychiatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu, 215123, P. R. China.
  • 4 Department of Medical Microbiology, School of Biology & Basic Medical Sciences, Medical College of Soochow University, No. 199, Ren Ai Road, Suzhou, Jiangsu, 215123, P. R. China. wushuyan@suda.edu.cn.
  • 5 Department of Medical Microbiology, School of Biology & Basic Medical Sciences, Medical College of Soochow University, No. 199, Ren Ai Road, Suzhou, Jiangsu, 215123, P. R. China. hruisdm@163.com.
  • # Contributed equally.
Abstract

Salmonella is one of the most important worldwide zoonotic pathogens. After invading a host orally, the bacteria break through the intestinal epithelial barrier for further invasion. Intestinal epithelial cells (IECs) play a crucial role in maintaining the integrity of the intestinal epithelial barrier. Necroptosis is considered one of the virulence strategies utilized by invasive Salmonella. Our previous work has shown that SpvB, an effector encoded by S. Typhimurium virulence plasmid (pSLT), promotes Bacterial translocation via the paracellular route. However, it is still unknown whether SpvB could promote Bacterial invasion through disrupting the integrity of IECs. Here, we demonstrated that SpvB promoted Necroptosis of IECs and contributed to the destruction of the intestinal barrier during Salmonella Infection. We found that SpvB enhanced the protein level of receptor-interacting protein kinase 3 (RIPK3) through inhibiting K48-linked poly-ubiquitylation of RIPK3 and the degradation of the protein in an autophagy-dependent manner. The abundant accumulation of RIPK3 upregulated the phosphorylation of MLKL, which contributed to Necroptosis. The damage to IECs ultimately led to the disruption of the intestinal barrier and aggravated Infection. In vivo, SpvB promoted the pathogenesis of Salmonella, favoring intestinal injury and colonic Necroptosis. Our findings reveal a novel function of Salmonella effector SpvB, which could facilitate salmonellosis by promoting Necroptosis, and broaden our understanding of the molecular mechanisms of Bacterial invasion.

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