Title | Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Hu 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 |
Journal | Mol Cell |
Volume | 66 |
Issue | 1 |
Pagination | 141-153.e6 |
Date Published | 2017 Apr 06 |
ISSN | 1097-4164 |
Keywords | Active 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. |
DOI | 10.1016/j.molcel.2017.03.008 |
Alternate Journal | Mol Cell |
PubMed ID | 28388439 |
PubMed Central ID | PMC5761061 |
Grant List | P30 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.