4.8 Article

Vitamin D Receptor Inhibits NLRP3 Activation by Impeding Its BRCC3-Mediated Deubiquitination

Journal

FRONTIERS IN IMMUNOLOGY
Volume 10, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2019.02783

Keywords

VDR; NLRP3 inflammasome; BRCC3; deubiquitinating; cytokines

Categories

Funding

  1. National Nature Science Foundation of China (NSFC) [81871310, 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]
  5. National Natural Science Foundation of China [81771773/91742116/81570499]

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The NLRP3 inflammasome is a multiprotein oligomer responsible for activation of the inflammatory response by promoting the maturation and secretion of the pro-inflammatory cytokines IL-1 beta and IL-18. Dysregulation of this inflammasome has been linked to several autoimmune diseases, indicating that NLRP3 is tightly regulated to prevent aberrant activation. The regulation of NLRP3 activation remains unclear. Here, we report the identification of vitamin D receptor (VDR) as a negative regulator of NLRP3 oligomerization and activation. VDR can physically bind NLRP3 and block the association of NLRP3 with BRCC3. When BRCC3-mediated deubiquitination of NLRP3 is inhibited by VDR, NLRP3 activation is subsequently inhibited. In the absence of VDR, caspase-1 activation and IL-1 beta release are increased in response to LPS-induced inflammation or alum-induced peritoneal inflammation, indicating that VDR is a negative regulator of NLRP3 inflammasome activation in vivo. In addition, vitamin D negatively regulates the NLRP3 inflammasome via VDR signaling to effectively inhibit IL-1 beta secretion. These studies demonstrate that VDR signaling constrains NLRP3 inflammasome activation and might be a potential treatment target for NLRP3 inflammasome-related diseases.

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