Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy.

TitleCelastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy.
Publication TypeJournal Article
Year of Publication2017
AuthorsHu M, Luo Q, Alitongbieke G, Chong S, Xu C, Xie L, Chen X, Zhang D, Zhou Y, Wang Z, Ye X, Cai L, Zhang F, Chen H, Jiang F, Fang H, Yang S, Liu J, Diaz-Meco MT, Su Y, Zhou H, Moscat J, Lin X, Zhang X-K
JournalMol Cell
Volume66
Issue1
Pagination141-153.e6
Date Published2017 Apr 06
ISSN1097-4164
KeywordsActive Transport, Cell Nucleus, Animals, Anti-Inflammatory Agents, Autophagy, Chemical and Drug Induced Liver Injury, Disease Models, Animal, Female, Genotype, HEK293 Cells, HeLa Cells, Hep G2 Cells, Humans, Ligands, Male, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Liver, Mitophagy, Nuclear Receptor Subfamily 4, Group A, Member 1, Phenotype, Protein Binding, Protein Interaction Domains and Motifs, RNA Interference, Sequestosome-1 Protein, Signal Transduction, TNF Receptor-Associated Factor 2, Transfection, Triterpenes, Ubiquitination
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.

DOI10.1016/j.molcel.2017.03.008
Alternate JournalMol Cell
PubMed ID28388439
PubMed Central IDPMC5761061
Grant ListP30 CA030199 / CA / NCI NIH HHS / United States
R01 CA172025 / CA / NCI NIH HHS / United States
R01 CA192642 / CA / NCI NIH HHS / United States
R21 CA179379 / CA / NCI NIH HHS / United States
Related Faculty: 
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700