title: Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy.
abstract: 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.
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Hu
authors.affiliation: Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, China State Oceanic Administration, Xiamen 361005, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Luo
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
authors.forename: Gulimiran
authors.initials: G
authors.lastname: Alitongbieke
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
authors.forename: Shuyi
authors.initials: S
authors.lastname: Chong
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
authors.forename: Chenting
authors.initials: C
authors.lastname: Xu
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xie
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
authors.forename: Duo
authors.initials: D
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, China State Oceanic Administration, Xiamen 361005, China.
authors.forename: Zhaokai
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Ye
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Cai
authors.affiliation: Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, China State Oceanic Administration, Xiamen 361005, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Biology Department, Xiamen Ocean College, Xiamen 361102, China.
authors.forename: Huibin
authors.initials: H
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
authors.forename: Fuquan
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, China State Oceanic Administration, Xiamen 361005, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Fang
authors.affiliation: Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, China State Oceanic Administration, Xiamen 361005, China.
authors.forename: Shanjun
authors.initials: S
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Cancer center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Cancer center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.affiliation: Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, China State Oceanic Administration, Xiamen 361005, China.
authors.forename: Xiangzhi
authors.initials: X
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Xiao-Kun
authors.initials: XK
authors.lastname: Zhang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D063306:Mitophagy / Q000187:drug effects*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D010641:Phenotype; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D000071456:Sequestosome-1 Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014315:Triterpenes / Q000378:metabolism / Q000494:pharmacology*; D054875:Ubiquitination / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D008024:Ligands; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D053978:Pentacyclic Triterpenes; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D047992:TNF Receptor-Associated Factor 2; C000622387:TRAF2 protein, mouse; D014315:Triterpenes; C050414:celastrol
keywords: Celastrol; Nur77; TR3; TRAF2; autophagy; inflammation; mitochondria; mitophagy; nuclear receptor; p62/SQSTM1