Vitamin D Receptor Inhibits NLRP3 Activation by Impeding Its BRCC3-Mediated Deubiquitination
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-1β and IL-18. Dysregulation of this inflammasome has been linked to several autoimmune diseases, indicating that NL...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02783/full |
| _version_ | 1818385717529673728 |
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| author | Zebing Rao Zebing Rao Xin Chen Xin Chen Junxian Wu Junxian Wu Mengjun Xiao Mengjun Xiao Jing Zhang Binghao Wang Lei Fang Hongjie Zhang Xiaoming Wang Xiaoming Wang Shuo Yang Shuo Yang Yunzi Chen Yunzi Chen Yunzi Chen |
| author_facet | Zebing Rao Zebing Rao Xin Chen Xin Chen Junxian Wu Junxian Wu Mengjun Xiao Mengjun Xiao Jing Zhang Binghao Wang Lei Fang Hongjie Zhang Xiaoming Wang Xiaoming Wang Shuo Yang Shuo Yang Yunzi Chen Yunzi Chen Yunzi Chen |
| author_sort | Zebing Rao |
| collection | DOAJ |
| description | 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-1β 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-1β 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-1β secretion. These studies demonstrate that VDR signaling constrains NLRP3 inflammasome activation and might be a potential treatment target for NLRP3 inflammasome-related diseases. |
| first_indexed | 2024-12-14T03:42:36Z |
| format | Article |
| id | doaj.art-f2478319c7e24661a4b15cfce0f0548a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T03:42:36Z |
| publishDate | 2019-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-f2478319c7e24661a4b15cfce0f0548a2022-12-21T23:18:26ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-12-011010.3389/fimmu.2019.02783475093Vitamin D Receptor Inhibits NLRP3 Activation by Impeding Its BRCC3-Mediated DeubiquitinationZebing Rao0Zebing Rao1Xin Chen2Xin Chen3Junxian Wu4Junxian Wu5Mengjun Xiao6Mengjun Xiao7Jing Zhang8Binghao Wang9Lei Fang10Hongjie Zhang11Xiaoming Wang12Xiaoming Wang13Shuo Yang14Shuo Yang15Yunzi Chen16Yunzi Chen17Yunzi Chen18Key Laboratory of Immune Microenvironment and Disease, Department of Immunology, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Antibody Techniques of Ministry of Health, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Immune Microenvironment and Disease, Department of Immunology, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Antibody Techniques of Ministry of Health, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Immune Microenvironment and Disease, Department of Immunology, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Antibody Techniques of Ministry of Health, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Immune Microenvironment and Disease, Department of Immunology, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Antibody Techniques of Ministry of Health, Nanjing Medical University, Nanjing, ChinaThe State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, ChinaJiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, ChinaJiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, ChinaDepartment of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaKey Laboratory of Immune Microenvironment and Disease, Department of Immunology, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Antibody Techniques of Ministry of Health, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Immune Microenvironment and Disease, Department of Immunology, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Antibody Techniques of Ministry of Health, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Immune Microenvironment and Disease, Department of Immunology, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Antibody Techniques of Ministry of Health, Nanjing Medical University, Nanjing, ChinaMedical Centre for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaThe 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-1β 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-1β 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-1β secretion. These studies demonstrate that VDR signaling constrains NLRP3 inflammasome activation and might be a potential treatment target for NLRP3 inflammasome-related diseases.https://www.frontiersin.org/article/10.3389/fimmu.2019.02783/fullVDRNLRP3 inflammasomeBRCC3deubiquitinatingcytokines |
| spellingShingle | Zebing Rao Zebing Rao Xin Chen Xin Chen Junxian Wu Junxian Wu Mengjun Xiao Mengjun Xiao Jing Zhang Binghao Wang Lei Fang Hongjie Zhang Xiaoming Wang Xiaoming Wang Shuo Yang Shuo Yang Yunzi Chen Yunzi Chen Yunzi Chen Vitamin D Receptor Inhibits NLRP3 Activation by Impeding Its BRCC3-Mediated Deubiquitination Frontiers in Immunology VDR NLRP3 inflammasome BRCC3 deubiquitinating cytokines |
| title | Vitamin D Receptor Inhibits NLRP3 Activation by Impeding Its BRCC3-Mediated Deubiquitination |
| title_full | Vitamin D Receptor Inhibits NLRP3 Activation by Impeding Its BRCC3-Mediated Deubiquitination |
| title_fullStr | Vitamin D Receptor Inhibits NLRP3 Activation by Impeding Its BRCC3-Mediated Deubiquitination |
| title_full_unstemmed | Vitamin D Receptor Inhibits NLRP3 Activation by Impeding Its BRCC3-Mediated Deubiquitination |
| title_short | Vitamin D Receptor Inhibits NLRP3 Activation by Impeding Its BRCC3-Mediated Deubiquitination |
| title_sort | vitamin d receptor inhibits nlrp3 activation by impeding its brcc3 mediated deubiquitination |
| topic | VDR NLRP3 inflammasome BRCC3 deubiquitinating cytokines |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.02783/full |
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