Binding of OTULIN to the PUB domain of HOIP controls NF-κB signaling

Mol Cell. 2014 May 8;54(3):349-61. doi: 10.1016/j.molcel.2014.03.016. Epub 2014 Apr 10.

Abstract

Linear ubiquitin chains are implicated in the regulation of the NF-κB pathway, immunity, and inflammation. They are synthesized by the LUBAC complex containing the catalytic subunit HOIL-1-interacting protein (HOIP) and are disassembled by the linear ubiquitin-specific deubiquitinase OTULIN. Little is known about the regulation of these opposing activities. Here we demonstrate that HOIP and OTULIN interact and act as a bimolecular editing pair for linear ubiquitin signals in vivo. The HOIP PUB domain binds to the PUB interacting motif (PIM) of OTULIN and the chaperone VCP/p97. Structural studies revealed the basis of high-affinity interaction with the OTULIN PIM. The conserved Tyr56 of OTULIN makes critical contacts with the HOIP PUB domain, and its phosphorylation negatively regulates this interaction. Functionally, HOIP binding to OTULIN is required for the recruitment of OTULIN to the TNF receptor complex and to counteract HOIP-dependent activation of the NF-κB pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / metabolism
  • Binding Sites
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism
  • Crystallography, X-Ray
  • Endopeptidases / chemistry*
  • Endopeptidases / metabolism
  • HeLa Cells
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Processing, Post-Translational
  • Protein Structure, Secondary
  • Receptors, Tumor Necrosis Factor / metabolism
  • Signal Transduction
  • Thermodynamics
  • Ubiquitin-Protein Ligases / chemistry*
  • Ubiquitin-Protein Ligases / metabolism
  • Valosin Containing Protein

Substances

  • Cell Cycle Proteins
  • NF-kappa B
  • Receptors, Tumor Necrosis Factor
  • RNF31 protein, human
  • Ubiquitin-Protein Ligases
  • Endopeptidases
  • gumby protein, human
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein