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

Stable Identifier
Reaction [binding]
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

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

Yuan, B, Weng, L, Lu, N, Zhang, Z, Liu, YJ, Bao, M

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

Zeng, S, Schenk, M, Parvatiyar, K, Cheng, G, Liu, YJ, Zaver, SA, Iyer, SS, Liu, ZJ, Ouyang, S, Zhang, Z, Modlin, RL, Teles, RM, Zhong, W, Jiang, Y

Nat. Immunol. 2012
Orthologous Events
Cite Us!