Vitamin D Receptor Inhibits NLRP3 Activation by Impeding Its BRCC3-Mediated Deubiquitination
Vitamin D Receptor Inhibits NLRP3 Activation by Impeding Its BRCC3-Mediated Deubiquitination
复制标题
维生素 D 受体通过阻止 BRCC3 介导的去泛素化来抑制 NLRP3 激活
DOI：
10.3389/fimmu.2019.02783
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发表时间：
2019-12-04
影响因子：
7.3
通讯作者：
Chen, Yunzi
中科院分区：
文献类型：
--
作者：
Rao, Zebing;Chen, Xin;Chen, Yunzi
NLRP 3炎性体是一种多蛋白寡聚体，通过促进促炎细胞因子IL-1 β和IL-18的成熟和分泌来激活炎症反应。这种炎性小体的失调与几种自身免疫性疾病有关，表明NLRP 3受到严格调节以防止异常激活。NLRP 3激活的调节仍不清楚。在这里，我们报告了维生素D受体（VDR）作为NLRP 3寡聚化和激活的负调节剂的鉴定。VDR可以物理结合NLRP 3并阻断NLRP 3与BRCC 3的结合。当VDR抑制BRCC 3介导的NLRP 3去泛素化时，NLRP 3活化随后被抑制。在不存在VDR的情况下，响应于LPS诱导的炎症或明矾诱导的腹膜炎症，半胱天冬酶-1活化和IL-1 β释放增加，表明VDR是体内NLRP 3炎性体活化的负调节剂。此外，维生素D通过VDR信号传导负向调节NLRP 3炎性体，以有效抑制IL-1 β分泌。这些研究表明，VDR信号抑制NLRP 3炎性小体激活，可能是NLRP 3炎性小体相关疾病的潜在治疗靶点。
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.