Acetylation-dependent signal transduction for type I interferon receptor

Cell. 2007 Oct 5;131(1):93-105. doi: 10.1016/j.cell.2007.07.034.


Cytokine-activated receptors initiate intracellular signaling by recruiting protein kinases that phosphorylate the receptors on tyrosine residues, thus enabling docking of SH2 domain-bearing activating factors. Here we report that in response to type 1 interferon (IFNalpha), IFNalpha receptors recruit cytoplasmic CREB-binding protein (CBP). By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9). IRF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2. All three components are acetylated by CBP. Remarkably, acetylation within the DNA-binding domain (DBD) of both IRF9 and STAT2 is critical for the ISGF3 complex activation and its associated antiviral gene regulation. These results have significant implications concerning the central role of acetylation in cytokine receptor signal transduction.

Publication types

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

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • CREB-Binding Protein / genetics
  • CREB-Binding Protein / metabolism*
  • HeLa Cells
  • Humans
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / genetics
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / metabolism
  • Interferon-alpha / metabolism*
  • Lysine / metabolism
  • Molecular Sequence Data
  • Protein Binding
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / metabolism*
  • Receptors, Interferon / genetics
  • Receptors, Interferon / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • STAT2 Transcription Factor / genetics
  • STAT2 Transcription Factor / metabolism
  • Sequence Alignment
  • Serine / metabolism
  • Signal Transduction / physiology*


  • IRF9 protein, human
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Interferon-alpha
  • RNA, Small Interfering
  • Receptors, Interferon
  • Recombinant Fusion Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT2 Transcription Factor
  • STAT2 protein, human
  • interferon receptor, type II
  • Receptor, Interferon alpha-beta
  • Serine
  • CREB-Binding Protein
  • Lysine