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

Mol Cell. 2017 Apr 6;66(1):141-153.e6. doi: 10.1016/j.molcel.2017.03.008.

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.

Keywords: Celastrol; Nur77; TR3; TRAF2; autophagy; inflammation; mitochondria; mitophagy; nuclear receptor; p62/SQSTM1.

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Anti-Inflammatory Agents / metabolism
  • Anti-Inflammatory Agents / pharmacology*
  • Autophagy / drug effects*
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / prevention & control*
  • Disease Models, Animal
  • Female
  • Genotype
  • HEK293 Cells
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Ligands
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria, Liver / drug effects*
  • Mitochondria, Liver / metabolism
  • Mitochondria, Liver / pathology
  • Mitophagy / drug effects*
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / deficiency
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Pentacyclic Triterpenes
  • Phenotype
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • RNA Interference
  • Sequestosome-1 Protein / genetics
  • Sequestosome-1 Protein / metabolism
  • Signal Transduction / drug effects
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 2 / metabolism*
  • Transfection
  • Triterpenes / metabolism
  • Triterpenes / pharmacology*
  • Ubiquitination / drug effects*

Substances

  • Anti-Inflammatory Agents
  • Ligands
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Pentacyclic Triterpenes
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • TNF Receptor-Associated Factor 2
  • TRAF2 protein, mouse
  • Triterpenes
  • celastrol