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

Parvatiyar, Michelle S.; Zhang, Zhiqiang; Teles, Rosane M. B.; Ouyang, Songying; Jiang, Yan; Iyer, Shankar S.; Zaver, Shivam A.; Schenk, Mirjam; Zeng, Siming; Zhong, Wenwan; Modlin, Robert L.; Liu, Yong Jun; Cheng, Genhong

doi:10.1038/ni.2460

Cited by 358 publications

(342 citation statements)

References 36 publications

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“…DDX41, like other DEAD-box helicases, has been shown to interact with and bind to nucleic acids and ATP for activation [37]. Specifically, by its DNA binding activity, DDX41 acts as a sensor of dsDNA and bacterial-derived cyclic di-nucleotides (CDN) (c-di-AMP, c-di-GMP) [40]. It also binds directly to numerous proteins within the interferon response pathway in the cytoplasm, including Stimulator of interferon genes (STING) [41].…”

Section: Ddx41 Protein Structurementioning

confidence: 99%

“…2b). Some of these include bacteria [produce c-di-GMP and c-di-AMP (CDN)], and poly(dA; dT) [40], invading dsDNA viruses (e.g., adenovirus, herpes virus and papillomavirus), and nearby cells that have released dsDNA fragments by necrosis [44]. The introduction of dsDNA and CDN into the cytoplasm occurs through pathogen-specific infection mechanisms, exosomes or receptor-mediated endocytosis [56].…”

Section: Ddx41 In the Sting-interferon Pathwaymentioning

confidence: 99%

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Myeloid neoplasms with germline DDX41 mutation

et al. 2017

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to DDX41 mutation and highlights how each of these suggest potential therapeutic opportunities through the use of pathway-specific inhibitors.Keywords DDX41 · Myeloid malignancy · Myelodysplastic syndrome · Acute myeloid leukemia · Germline mutation · Predisposition Familial predisposition to myeloid neoplasmsMyeloid neoplasms are a heterogeneous group of diseases encompassing myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), all of which are characterized by abnormal growth and development of cells of the myeloid blood lineage. These disease groups can be further sub-categorized by a number of different morphological and molecular approaches which may correlate with responses to specific treatments [1]. AML and MDS Abstract Recently, DDX41 mutations have been identified both as germline and acquired somatic mutations in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. The majority of germline mutations are frameshift mutations suggesting loss of function with DDX41 acting as a tumor suppressor, and there is a common somatic missense mutation found in a majority of germline mutated tumors. Clinically, DDX41 mutations lead to development of high-risk MDS at an age similar to that observed in sporadic cohorts, presenting a unique challenge to hematologists in recognizing the familial context. Functionally, DDX41 has been shown to contribute to multiple pathways and processes including mRNA splicing, innate immunity and rRNA processing. Mutations in DDX41 result in aberrations to each of these in ways that could potentially impact on tumorigenesis-initiation, maintenance or progression. This review discusses the various molecular, clinical and biological aspects of myeloid malignancy predisposition due

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Section: Ddx41 Protein Structurementioning

confidence: 99%

Section: Ddx41 In the Sting-interferon Pathwaymentioning

confidence: 99%

Myeloid neoplasms with germline DDX41 mutation

et al. 2017

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“…RIG-I 11 and melanoma differentiation-associated protein 5 (MDA5) 12 can recognize viral dsRNA and recruit the CARD containing adaptor protein MAVS (also known as IPS-1, CARDIF or VISA), leading to IRF activation and the production of type I IFN. In addition to RLRs, a group of cytosolic DNA sensors such as cyclic GMP-AMP synthase (cGAS), [13][14][15] absent in melanoma 2 (AIM2), 16,17 DDX41, 18,19 Rad50, 20,21 LRRFIP1, 22 DNA-dependent activator of IRFs (DAI), 23 as well as various RNA sensors such as IFN-induced protein with tetratricopeptide repeats 1 (IFIT1) 24 also play potent roles in inducing antiviral immune response, respectively via the adaptor protein stimulator of interferon genes (STING, also known as MITA, ERIS or MPYS) or the MAVS pathway. cGAS, which was previously thought to recognize cytoplasmic dsDNA over 40 bp in a sequence-independent manner, is recently shown to recognize unpaired guanosines flanking short (12-20 bp) dsDNA (Y-form DNA) found in human immunodeficiency virus type 1 to induce type I IFN production.…”

Section: Introductionmentioning

confidence: 99%

Cellular and molecular regulation of innate inflammatory responses

2016

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“…C-di-GMP also controls biofilm formation, exopolysaccaride production, toxin production and related outcomes, therefore c-di-GMP can be considered to be a second messenger in bacteria [11][12][13]. In addition, our group recently reported that c-di-GMP can stimulate the innate immune system [14] and, given the fact that c-di-GMP binds to DDX41 in the cytosol, can form a complex with STING, send the signal via the TBK1-IRF3 pathway and activate type I interferons [15,16]. Therefore the receptor for c-di-GMP is DDX41 in the cytosol is different from known adjuvants such as polyIC (toll like receptor 3 on the cell surface) and CpG oligonucleotides (toll like receptor on endosome).…”

Section: Introductionmentioning

confidence: 99%

A new adjuvant delivery system ‘cyclic di-GMP/YSK05 liposome’ for cancer immunotherapy

Miyabe

Hyodo

Nakamura

et al. 2014

Journal of Controlled Release

139

108

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Cyclic dinucleotides are of importance in the field of microbiology and immunology. They function as second messengers and are thought to participate in the signal transduction of cytosolic DNA immune responses. One such dinucleotide, cyclic di-GMP (c-di-GMP), stimulates the immune system. C-di-GMP is thought to be recognized by ATP dependant RNA helicase (DDX41) in the cytosol, forms a complex with the Stimulator of interferon genes protein (STING), triggers the signal via the tank binding kinase 1 -interferon regulatory factor 3 (TBK1-IRF3) pathway and induces the production of type I interferons. Therefore c-di-GMP can be thought of as a new class of adjuvant. However, because c-di-GMP contains two phosphate groups, this prevents its use as the adjuvant because it cannot pass through the cell membrane, even though the target molecule of c-di-GMP is located in the cytoplasm.Our group have been developing a series of liposomal drug delivery systems and recently investigated YSK05 which is a synthetic lipid with a pH sensitivity and has a high fusogenicity. We utilized this lipid as a carrier to send c-di-GMP into the cytosol to then use c-di-GMP as an adjuvant. Based on screening experiments, YSK05/POPE/Cholesterol = 40/30/30 was found to induce IFN-β in Raw264.7 cells. The induction of IFN-β from c-di-GMP liposomes was inhibited by adding BX795, a TBK1 inhibitor, indicating that the production of IFN-β caused the activation of STING-TBK1 pathway. C-di-GMP liposomes also showed significantly higher levels of expression of CD80, CD86 and MHC class I. The c-di-GMP/YSK05 liposome facilitated antigen specific cytotoxic T cell activity and the inhibition of tumor growth in a mouse model. These findings indicate that c-di-GMP/YSK05 liposomes could be used, not only to transfer c-di-GMP to the cytosol and induce an innate immune system but also as a platform for investigating the mechanism of immune sensing with cyclic dinucleotides in vitro and in vivo.

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

Cited by 358 publications

References 36 publications

Myeloid neoplasms with germline DDX41 mutation

Myeloid neoplasms with germline DDX41 mutation

Cellular and molecular regulation of innate inflammatory responses

A new adjuvant delivery system ‘cyclic di-GMP/YSK05 liposome’ for cancer immunotherapy

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