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

Mengjie Hu1, Qiang Luo2, Gulimiran Alitongbieke1

  • 1School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.

Molecular Cell
|April 8, 2017
PubMed

Insights

Celastrol, an anti-inflammatory compound, targets the Nur77 protein to reduce inflammation by promoting the clearance of damaged mitochondria through autophagy. This process involves Nur77 interacting with TRAF2 and p62/SQSTM1 proteins.

Area of Science:

  • Cellular Biology
  • Immunology
  • Molecular Medicine

Background:

  • Mitochondria are crucial for cellular processes including apoptosis, autophagy, immunity, and inflammation.
  • Nur77, an orphan nuclear receptor, has been previously implicated in inducing apoptosis via mitochondrial pathways.

Purpose of the Study:

  • To investigate the mechanism by which celastrol, a pentacyclic triterpene, exerts its anti-inflammatory effects.
  • To elucidate the role of Nur77 as an intracellular target for celastrol in regulating inflammation and autophagy.

Main Methods:

  • Investigated the interaction between celastrol and Nur77 using biochemical assays.
  • Tracked Nur77 translocation from the nucleus to mitochondria under inflammatory conditions.
  • Analyzed the interaction of Nur77 with TRAF2 and p62/SQSTM1, including ubiquitination events.
  • Assessed the role of Nur77 in celastrol-induced autophagy and inflammation reduction.

Main Results:

  • Celastrol binds to Nur77, promoting its translocation to mitochondria.
  • Nur77 interacts with TRAF2 at mitochondria, inhibiting TRAF2 ubiquitination and inducing Nur77 ubiquitination.
  • Ubiquitinated Nur77 at mitochondria facilitates their clearance via autophagy, involving p62/SQSTM1.
  • Celastrol's anti-inflammatory and autophagy-inducing effects are dependent on Nur77.

Conclusions:

  • Nur77 is a key intracellular target for celastrol's anti-inflammatory actions.
  • Celastrol induces autophagy-dependent clearance of inflamed mitochondria through a Nur77-mediated pathway.
  • This mechanism highlights a novel strategy for alleviating inflammation by targeting mitochondrial quality control.
Keywords:
CelastrolNur77TR3TRAF2autophagyinflammationmitochondriamitophagynuclear receptorp62/SQSTM1

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