The Helicase DDX41 Recognizes the Bacterial Secondary Messengers Cyclic di-GMP and Cyclic di-AMP to Activate a Type I Interferon Immune Response

Nat Immunol. 2012 Dec;13(12):1155-61. doi: 10.1038/ni.2460. Epub 2012 Nov 11.

Abstract

The induction of type I interferons by the bacterial secondary messengers cyclic di-GMP (c-di-GMP) or cyclic di-AMP (c-di-AMP) is dependent on a signaling axis that involves the adaptor STING, the kinase TBK1 and the transcription factor IRF3. Here we identified the heliase DDX41 as a pattern-recognition receptor (PRR) that sensed both c-di-GMP and c-di-AMP. DDX41 specifically and directly interacted with c-di-GMP. Knockdown of DDX41 via short hairpin RNA in mouse or human cells inhibited the induction of genes encoding molecules involved in the innate immune response and resulted in defective activation of STING, TBK1 and IRF3 in response to c-di-GMP or c-di-AMP. Our results suggest a mechanism whereby c-di-GMP and c-di-AMP are detected by DDX41, which forms a complex with STING to signal to TBK1-IRF3 and activate the interferon response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / metabolism
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • Dinucleoside Phosphates / metabolism*
  • Humans
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I / immunology*
  • Listeria monocytogenes / immunology*
  • Listeria monocytogenes / metabolism*
  • Macrophages / immunology
  • Membrane Proteins / metabolism
  • Mice
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Pattern Recognition / genetics
  • Receptors, Pattern Recognition / metabolism*
  • Second Messenger Systems
  • Signal Transduction

Substances

  • Dinucleoside Phosphates
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Membrane Proteins
  • RNA, Small Interfering
  • Receptors, Pattern Recognition
  • STING protein, human
  • cyclic diadenosine phosphate
  • bis(3',5')-cyclic diguanylic acid
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • DDX41 protein, human
  • DEAD-box RNA Helicases
  • Cyclic GMP