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

被引：398

作者：

Hu, Mengjie ^{[1
]}

Luo, Qiang ^{[2
]}

Alitongbieke, Gulimiran ^{[1
]}

Chong, Shuyi ^{[1
]}

Xu, Chenting ^{[1
]}

Xie, Lei ^{[1
]}

Chen, Xiaohui ^{[1
]}

Zhang, Duo ^{[1
]}

Zhou, Yuqi ^{[1
]}

Wang, Zhaokai ^{[2
]}

Ye, Xiaohong ^{[1
]}

Cai, Lijun ^{[1
]}

Zhang, Fang ^{[2
]}

Chen, Huibin ^{[3
]}

Jiang, Fuquan ^{[1
]}

Fang, Hui ^{[2
]}

Yang, Shanjun ^{[2
]}

Liu, Jie ^{[1
]}

Diaz-Meco, Maria T. ^{[4
]}

Su, Ying ^{[1
,4
]}

Zhou, Hu ^{[1
]}

Moscat, Jorge ^{[4
]}

Lin, Xiangzhi ^{[2
]}

Zhang, Xiao-kun ^{[1
,4
]}

机构：

[1] Xiamen Univ, Sch Pharmaceut Sci, Fujian Prov Key Lab Innovat Drug Target Res, Xiamen 361102, Peoples R China

[2] China State Ocean Adm, Engn Res Ctr Marine Biol Resource Comprehens Util, Inst Oceanog 3, Xiamen 361005, Peoples R China

[3] Xiamen Ocean Coll, Dept Biol, Xiamen 361102, Peoples R China

[4] Sanford Burnham Prebys Med Discovery Inst, Ctr Canc, La Jolla, CA 92037 USA

来源：

MOLECULAR CELL | 2017年 / 66卷 / 01期

基金：

美国国家卫生研究院;

关键词：

NF-KAPPA-B; RXR-ALPHA; TRANSCRIPTION FACTORS; NUCLEAR; ACTIVATION; EXPRESSION; OBESITY; NR4A1; COACTIVATOR; RECRUITMENT;

D O I：

10.1016/j.molcel.2017.03.008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：141 / +

页数：19

共 71 条

[1]

Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2 [J].