Downregulation of active IKK beta by Ro52-mediated autophagy

Mol Immunol. 2010 Aug;47(14):2378-87. doi: 10.1016/j.molimm.2010.05.004. Epub 2010 Jun 2.

Abstract

Upon activation, NF-kappaB translocates into the nucleus and initiates many biological events. This NF-kappaB signaling is mainly induced by the protein kinase IKK beta. Early in this signaling pathway, IKK beta is phosphorylated for activation by several factors, such as pro-inflammatory cytokines and the Tax oncoprotein of human T-cell leukemia virus type 1 (HTLV-1). In cells expressing Tax protein, IKK beta is persistently phosphorylated, which chronically activates NF-kappaB signaling. But the active IKK beta is conjugated with a monoubiquitin by the E3 ubiquitin ligase Ro52, and the IKK beta-induced NF-kappaB signaling is downregulated. However, the mechanism of the downregulation has been unknown. Here, we show that Ro52-mediated monoubiquitination is involved in the subcellular translocation of active IKK beta to autophagosomes. Furthermore, using reporter assays, we show that Ro52 suppresses IKK beta-induced NF-kappaB signaling and that this suppression is blocked by an autophagy inhibitor. These results suggest that Ro52-mediated monoubiquitination plays a critical role in the downregulation of active IKK beta through autophagy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Substitution
  • Autophagy / physiology*
  • Biological Transport, Active
  • Cell Line
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Humans
  • I-kappa B Kinase / chemistry
  • I-kappa B Kinase / metabolism*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Models, Biological
  • Mutagenesis, Site-Directed
  • NF-kappa B / metabolism
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phagosomes / metabolism
  • Phosphorylation
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Ribonucleoproteins / chemistry
  • Ribonucleoproteins / genetics
  • Ribonucleoproteins / metabolism*
  • Signal Transduction
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • DNA-Binding Proteins
  • Luminescent Proteins
  • NF-kappa B
  • Nuclear Proteins
  • Recombinant Fusion Proteins
  • Ribonucleoproteins
  • SS-A antigen
  • enhanced green fluorescent protein
  • red fluorescent protein
  • Green Fluorescent Proteins
  • Ubiquitin-Protein Ligases
  • I-kappa B Kinase