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Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy.
Hu, Mengjie; Luo, Qiang; Alitongbieke, Gulimiran; Chong, Shuyi; Xu, Chenting; Xie, Lei; Chen, Xiaohui; Zhang, Duo; Zhou, Yuqi; Wang, Zhaokai; Ye, Xiaohong; Cai, Lijun; Zhang, Fang; Chen, Huibin; Jiang, Fuquan; Fang, Hui; Yang, Shanjun; Liu, Jie; Diaz-Meco, Maria T; Su, Ying; Zhou, Hu; Moscat, Jorge; Lin, Xiangzhi; Zhang, Xiao-Kun.
Afiliação
  • Hu M; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
  • Luo Q; Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, China State Oceanic Administration, Xiamen 361005, China.
  • Alitongbieke G; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
  • Chong S; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
  • Xu C; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
  • Xie L; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
  • Chen X; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
  • Zhang D; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
  • Zhou Y; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
  • Wang Z; Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, China State Oceanic Administration, Xiamen 361005, China.
  • Ye X; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
  • Cai L; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
  • Zhang F; Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, China State Oceanic Administration, Xiamen 361005, China.
  • Chen H; Biology Department, Xiamen Ocean College, Xiamen 361102, China.
  • Jiang F; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
  • Fang H; Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, China State Oceanic Administration, Xiamen 361005, China.
  • Yang S; Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, China State Oceanic Administration, Xiamen 361005, China.
  • Liu J; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
  • Diaz-Meco MT; Cancer center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • Su Y; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China; Cancer center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • Zhou H; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
  • Moscat J; Cancer center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • Lin X; Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, China State Oceanic Administration, Xiamen 361005, China.
  • Zhang XK; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China; Cancer center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: xzhang@sbpdiscovery.org.
Mol Cell ; 66(1): 141-153.e6, 2017 Apr 06.
Article em En | MEDLINE | ID: mdl-28388439
Mitochondria play an integral role in cell death, autophagy, immunity, and inflammation. We previously showed that Nur77, an orphan nuclear receptor, induces apoptosis by targeting mitochondria. Here, we report that celastrol, a potent anti-inflammatory pentacyclic triterpene, binds Nur77 to inhibit inflammation and induce autophagy in a Nur77-dependent manner. Celastrol promotes Nur77 translocation from the nucleus to mitochondria, where it interacts with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase important for inflammatory signaling. The interaction is mediated by an LxxLL motif in TRAF2 and results not only in the inhibition of TRAF2 ubiquitination but also in Lys63-linked Nur77 ubiquitination. Under inflammatory conditions, ubiquitinated Nur77 resides at mitochondria, rendering them sensitive to autophagy, an event involving Nur77 interaction with p62/SQSTM1. Together, our results identify Nur77 as a critical intracellular target for celastrol and unravel a mechanism of Nur77-dependent clearance of inflamed mitochondria to alleviate inflammation.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autofagia / Triterpenos / Mitocôndrias Hepáticas / Fator 2 Associado a Receptor de TNF / Ubiquitinação / Doença Hepática Induzida por Substâncias e Drogas / Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares / Mitofagia / Anti-Inflamatórios Tipo de estudo: Prognostic_studies Idioma: En Revista: Mol Cell Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2017 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autofagia / Triterpenos / Mitocôndrias Hepáticas / Fator 2 Associado a Receptor de TNF / Ubiquitinação / Doença Hepática Induzida por Substâncias e Drogas / Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares / Mitofagia / Anti-Inflamatórios Tipo de estudo: Prognostic_studies Idioma: En Revista: Mol Cell Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2017 Tipo de documento: Article País de afiliação: China