Involvement of A20 in the Molecular Switch That Activates the Non-Canonical NF-кB Pathway

Sci Rep. 2013;3:2568. doi: 10.1038/srep02568.


The non-canonical NF-κB pathway is crucial for the immune system. A critical event in activation of the non-canonical pathway is the attenuation of NF-κB-inducing kinase (NIK) degradation, which is promoted by continuous polyubiquitination of NIK catalyzed by the NIK ubiquitin-ligase complex composed of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2), TNF receptor-associated factor 2 (TRAF2), and TRAF3. However, the molecular mechanism of stimulation-dependent NIK stabilization remains poorly understood. Here, we show that A20, a ubiquitin-editing enzyme, promotes efficient activation of the non-canonical pathway independent of its catalytic activity. A20 directly binds to cIAP1 through the seventh zinc finger of A20, resulting in dissociation of the TRAF2/TRAF3 interaction, thereby inactivating the ligase complex to stabilize NIK. Given that A20 negatively regulates the canonical pathway, A20 is likely involved in the molecular switch that promotes the transition from canonical to non-canonical activation for proper control of the immune system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Binding Proteins / metabolism*
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • NF-kappa B / metabolism*
  • Nuclear Proteins / metabolism*
  • Signal Transduction / physiology
  • TNF Receptor-Associated Factor 2 / metabolism*
  • TNF Receptor-Associated Factor 3 / metabolism*
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Ubiquitination / physiology*
  • Ubiquitins / metabolism*


  • DNA-Binding Proteins
  • Inhibitor of Apoptosis Proteins
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Nuclear Proteins
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 3
  • Ubiquitins
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3