Mapping a dynamic innate immunity protein interaction network regulating type I interferon production

Immunity. 2011 Sep 23;35(3):426-40. doi: 10.1016/j.immuni.2011.06.014. Epub 2011 Sep 8.

Abstract

To systematically investigate innate immune signaling networks regulating production of type I interferon, we analyzed protein complexes formed after microbial recognition. Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon (HI5) of 401 unique interactions; 21% of interactions were modulated by RNA, DNA, or LPS. Overexpression and depletion analyses identified 22 unique genes that regulated NF-κB and ISRE reporter activity, viral replication, or virus-induced interferon production. Detailed mechanistic analysis defined a role for mind bomb (MIB) E3 ligases in K63-linked ubiquitination of TBK1, a kinase that phosphorylates IRF transcription factors controlling interferon production. Mib genes selectively controlled responses to cytosolic RNA. MIB deficiency reduced antiviral activity, establishing the role of MIB proteins as positive regulators of antiviral responses. The HI5 provides a dynamic physical and regulatory network that serves as a resource for mechanistic analysis of innate immune signaling.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • HEK293 Cells
  • Humans
  • Immunity, Innate*
  • Interferon Type I / genetics
  • Interferon Type I / immunology*
  • Mice
  • Protein Interaction Mapping*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / immunology
  • Proteomics
  • Ubiquitination
  • Virus Diseases / immunology
  • Viruses / immunology

Substances

  • Interferon Type I
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human