1. Academic Validation
  2. A detrimental role of NLRP6 in host iron metabolism during Salmonella infection

A detrimental role of NLRP6 in host iron metabolism during Salmonella infection

  • Redox Biol. 2022 Feb;49:102217. doi: 10.1016/j.redox.2021.102217.
Qifeng Deng 1 Sidi Yang 2 Lanqing Sun 1 Kai Huang 3 Kedi Dong 1 Yuan Zhu 1 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, PR China.
  • 2 Centre for Infection and Immunity Studies (CIIS), School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, 518107, PR China.
  • 3 Cambridge-Suda Genomic Resource Center, Jiangsu Key Laboratory of Neuropsychiatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu, 215123, PR 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, PR China. Electronic address: 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, PR China. Electronic address: hruisdm@163.com.
Abstract

Maintaining host iron homeostasis is an essential component of nutritional immunity responsible for sequestrating iron from pathogens and controlling Infection. Nucleotide-oligomerization domain-like receptors (NLRs) contribute to cytoplasmic sensing and antimicrobial response orchestration. However, it remains unknown whether and how NLRs may regulate host iron metabolism, an important component of nutritional immunity. Here, we demonstrated that NLRP6, a member of the NLR family, has an unconventional role in regulating host iron metabolism that perturbs host resistance to Bacterial infection. NLRP6 deficiency is advantageous for maintaining cellular iron homeostasis in both macrophages and enterocytes through increasing the unique iron exporter ferroportin-mediated iron efflux in a nuclear factor erythroid-derived 2-related factor 2 (NRF2)-dependent manner. Additional studies uncovered a novel mechanism underlying NRF2 regulation and operating through NLRP6/Akt interaction and that causes a decrease in Akt phosphorylation, which in turn reduces NRF2 nuclear translocation. In the absence of NLRP6, increased Akt activation promotes NRF2/KEAP1 dissociation via increasing mTOR-mediated p62 phosphorylation and downregulates KEAP1 transcription by promoting FOXO3A phosphorylation. Together, our observations provide new insights into the mechanism of nutritional immunity by revealing a novel function of NLRP6 in regulating iron metabolism, and suggest NLRP6 as a therapeutic target for limiting Bacterial iron acquisition.

Keywords

Ferroportin; Iron metabolism; NLRP6; Nutritional immunity; Salmonella Typhimurium.

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