4.7 Article

Vitamin D receptor enhances the NLRC4 inflammasome activation by promoting NAIPs-NLRC4 association

期刊

EMBO REPORTS
卷 23, 期 9, 页码 -

出版社

WILEY
DOI: 10.15252/embr.202254611

关键词

NLRC4 inflammasome; S; Typhimurium infection; VDR

资金

  1. National Nature Science Foundation of China (NSFC) [81871310, 82171723, 81371759]
  2. Natural Science Foundation of Jiangsu Higher Education Institutions of China [17KJA310002]
  3. Key Project of a Science and Technology Development Fund from Nanjing Medical University [2017NJMUCX003]
  4. Nanjing Medical University [2014RC02]

向作者/读者索取更多资源

Inflammasomes are important cytosolic complexes that defend against bacterial pathogens. This study demonstrates that the vitamin D receptor (VDR) is a critical regulator of NLRC4 inflammasome activation, promoting the association between NAIPs and NLRC4.
Inflammasomes are cytosolic multiprotein complexes that initiate host defense against bacterial pathogens. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family caspase-associated recruitment domain-containing protein 4 (NLRC4) inflammasomes plays a critical role in the inflammatory response against intracellular bacterial infection. The NLR family apoptosis inhibitory proteins (NAIPs) detect Flagellin or type III secretion system (T3SS) microbial components to activate NLRC4 inflammasome. However, the underlying mechanism of NLRC4 inflammasome activation is not completely understood. Here, we show that the vitamin D receptor (VDR) is an essential immunological regulator of the NLRC4 inflammasome. Conditional VDR knockout mice (VDRflox/flox lyz2-Cre) exhibited impaired clearance of pathogens after acute Salmonella Typhimurium infection leading to poor survival. In macrophages, VDR deficiency reduced caspase-1 activation and IL-1 beta secretion upon S. Typhimurium infection. For NAIPs act as upstream sensors for NLRC4 inflammasome assembly, the further study demonstrated that VDR promoted the NAIP-NLRC4 association and triggered NAIP-NLRC4 inflammasome activation, not NLRP3 activation. Moreover, Lys123 residue of VDR is identified as the critical amino acid for VDR-NLRC4 interaction, and the mutant VDR (K123A) effectively attenuates the NLRC4 inflammasome activation. Together, our findings suggest that VDR is a critical regulator of NAIPs-NLRC4 inflammasome activation, mediating innate immunity against bacterial infection.

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