The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response.

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.

• Authors: Kislay Parvatiyar, Zhiqiang Zhang, Rosane M Teles, Songying Ouyang, Yan Jiang, Shankar S Iyer, Shivam A Zaver, Mirjam Schenk, Shang Zeng, Wenwan Zhong, Zhi-Jie Liu, Robert L Modlin, Yong-jun Liu, Genhong Cheng
• Journal: Nature immunology (Nat Immunol) Vol. 13 Issue 12 Pg. 1155-61 (Dec 2012) ISSN: 1529-2916 [Electronic] United States
• PMID: 23142775 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Dinucleoside Phosphates
• IRF3 protein, human
• Interferon Regulatory Factor-3
• Interferon Type I
• Membrane Proteins
• RNA, Small Interfering
• Receptors, Pattern Recognition
• STING1 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

Topics

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