Structural basis of STAT2 recognition by IRF9 reveals molecular insights into ISGF3 function

Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E601-E609. doi: 10.1073/pnas.1718426115. Epub 2018 Jan 9.

Abstract

Cytokine signaling through the JAK/STAT pathway controls multiple cellular responses including growth, survival, differentiation, and pathogen resistance. An expansion in the gene regulatory repertoire controlled by JAK/STAT signaling occurs through the interaction of STATs with IRF transcription factors to form ISGF3, a complex that contains STAT1, STAT2, and IRF9 and regulates expression of IFN-stimulated genes. ISGF3 function depends on selective interaction between IRF9, through its IRF-association domain (IAD), with the coiled-coil domain (CCD) of STAT2. Here, we report the crystal structures of the IRF9-IAD alone and in a complex with STAT2-CCD. Despite similarity in the overall structure among respective paralogs, the surface features of the IRF9-IAD and STAT2-CCD have diverged to enable specific interaction between these family members. We derive a model for the ISGF3 complex bound to an ISRE DNA element and demonstrate that the observed interface between STAT2 and IRF9 is required for ISGF3 function in cells.

Keywords: IRF transcription factor; JAK/STAT signaling; STAT2; crystal structure; innate immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / genetics
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / metabolism*
  • Janus Kinases / metabolism
  • Mice
  • Point Mutation
  • Protein Domains
  • STAT2 Transcription Factor / genetics
  • STAT2 Transcription Factor / metabolism*
  • Signal Transduction

Substances

  • IRF9 protein, human
  • IRF9 protein, mouse
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • STAT2 Transcription Factor
  • Janus Kinases

Associated data

  • PDB/5OEM
  • PDB/5OEN