Reactome | DDX41 binds bacterial c-di-AMP, c-di-GMP

DDX41 binds bacterial c-di-AMP, c-di-GMP

Stable Identifier

R-HSA-9013869

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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DDX41 binds bacterial c-di-AMP, c-di-GMP

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DEAD-Box Helicase 41 (DDX41) is the helicase that senses exogenous DNA in human and mouse cells (Zhang Z et al. 2011, Parvatiyar K et al. 2012). DDX41 was also reported to sense and interact with bacterial secondary messengers cyclic di-GMP or cyclic di-AMP (Parvatiyar K et al. 2012). Upon ligand recognition DDX41 interacts with STING to activate TBK1/IRF3 leading to type 1 IFN production (Zhang Z et al. 2011; Lee KG et al. 2015). Mutagenesis analysis with DDX41 deletion constructs revealed that the central DEAD-box domain of DDX41 mediated the binding with DNA (Zhang Z et al. 2011, Parvatiyar K et al. 2012). Knockdown of DDX41 or STING in human cells (THP-1 and PBMC cells) and mouse dendritic cells significantly reduced the cytokine production in response to pathogen-derived DNA or poly(dG:dC) (Zhang Z et al. 2011, Parvatiyar K et al. 2012). DDX41 localized together with STING in the cytoplasm when both DDX41 and STING were co-expressed in HEK293T cells (Zhang Z et al. 2011). Mouse Ddx41 was found to bind Sting and Tbk1 in both resting and poly(dA:dT)-stimulated mouse splenic myeloid dendritic cell (D2SC mDCs) (Zhang Z et al. 2011). Tyr364 and Tyr414 of DDX41 were found to be critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identified Tyr414 as the BTK phosphorylation site (Lee KG et al. 2015). Ddx41-Sting interaction was also observed in c-di-GMP- or c-di-AMP-treated D2SC cells (Parvatiyar K et al. 2012). Moreover, knockdown of Ddx41 or Sting inhibited phosphorylation of Tbk1, Irf3, p65 subunit of NF-kappaB and other signal transducers in DNA-stimulated mouse bone marrow-derived (BMDCs) and D2SC cells (Zhang Z et al. 2011, Parvatiyar K et al. 2012). Collectively, these data suggest that DNA triggers DDX41 downstream signaling to type I interferon in a STING-dependent manner.

The E3 ubiquitin ligase TRIM21 was reported to promote the K48-linked ubiquitination and degradation of DDX41 leading to downregulation of the type I interferon production in mouse mDC and human monocytes THP-1 (Zhang Z et al. 2013).

Literature References

PubMed ID	Title	Journal	Year
23222971	The E3 ubiquitin ligase TRIM21 negatively regulates the innate immune response to intracellular double-stranded DNA Zhang, Z, Bao, M, Lu, N, Weng, L, Yuan, B, Liu, YJ	Nat. Immunol.	2012
23142775	The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response Parvatiyar, K, Zhang, Z, Teles, RM, Ouyang, S, Jiang, Y, Iyer, SS, Zaver, SA, Schenk, M, Zeng, S, Zhong, W, Liu, ZJ, Modlin, RL, Liu, YJ, Cheng, G	Nat. Immunol.	2012