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

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          Abstract

          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 involving the STING adaptor, TBK1 kinase and IRF3 transcription factor. Here we identified the helicase DEAD box polypeptide 41 (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 shRNA in murine or human cells inhibited the induction of innate immune genes and resulted in defective STING, TBK1 and IRF3 activation in response to c-di-GMP or c-di-AMP. These results suggest a mechanism whereby c-di-GMP and c-di-AMP are detected by the DDX41 PRR, which complexes with STING to signal to TBK1-IRF3 and activate the interferon response.

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          Recognition of microorganisms and activation of the immune response.

          Ruslan Medzhitov (2007)
          The mammalian immune system has innate and adaptive components, which cooperate to protect the host against microbial infections. The innate immune system consists of functionally distinct 'modules' that evolved to provide different forms of protection against pathogens. It senses pathogens through pattern-recognition receptors, which trigger the activation of antimicrobial defences and stimulate the adaptive immune response. The adaptive immune system, in turn, activates innate effector mechanisms in an antigen-specific manner. The connections between the various immune components are not fully understood, but recent progress brings us closer to an integrated view of the immune system and its function in host defence.
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            ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization.

            Xiang Zhou, Yi Feng Zhou, Zhonghe Zhai … (2009)
            We report here the identification and characterization of a protein, ERIS, an endoplasmic reticulum (ER) IFN stimulator, which is a strong type I IFN stimulator and plays a pivotal role in response to both non-self-cytosolic RNA and dsDNA. ERIS (also known as STING or MITA) resided exclusively on ER membrane. The ER retention/retrieval sequence RIR was found to be critical to retain the protein on ER membrane and to maintain its integrity. ERIS was dimerized on innate immune challenges. Coumermycin-induced ERIS dimerization led to strong and fast IFN induction, suggesting that dimerization of ERIS was critical for self-activation and subsequent downstream signaling.
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              Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response.

              Tatsuya Saitoh, Naonobu Fujita, Takuya Hayashi … (2009)
              Microbial nucleic acids are critical for the induction of innate immune responses, a host defense mechanism against infection by microbes. Recent studies have indicated that double-stranded DNA (dsDNA) induces potent innate immune responses via the induction of type I IFN (IFN) and IFN-inducible genes. However, the regulatory mechanisms underlying dsDNA-triggered signaling are not fully understood. Here we show that the translocation and assembly of the essential signal transducers, stimulator of IFN genes (STING) and TANK-binding kinase 1 (TBK1), are required for dsDNA-triggered innate immune responses. After sensing dsDNA, STING moves from the endoplasmic reticulum (ER) to the Golgi apparatus and finally reaches the cytoplasmic punctate structures to assemble with TBK1. The addition of an ER-retention signal to the C terminus of STING dampens its ability to induce antiviral responses. We also show that STING co-localizes with the autophagy proteins, microtubule-associated protein 1 light chain 3 (LC3) and autophagy-related gene 9a (Atg9a), after dsDNA stimulation. The loss of Atg9a, but not that of another autophagy-related gene (Atg7), greatly enhances the assembly of STING and TBK1 by dsDNA, leading to aberrant activation of the innate immune response. Hence Atg9a functions as a regulator of innate immunity following dsDNA stimulation as well as an essential autophagy protein. These results demonstrate that dynamic membrane traffic mediates the sequential translocation and assembly of STING, both of which are essential processes required for maximal activation of the innate immune response triggered by dsDNA.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100941354
                Journal ID (pubmed-jr-id): 21750
                Journal ID (nlm-ta): Nat Immunol
                Journal ID (iso-abbrev): Nat. Immunol.
                Title: Nature immunology
                ISSN (Print): 1529-2908
                ISSN (Electronic): 1529-2916
                Publication date Nihms-submitted: 12 October 2012
                Publication date (Electronic): 11 November 2012
                Publication date (Print): December 2012
                Publication date PMC-release: 01 June 2013
                Volume: 13
                Issue: 12
                Pages: 1155-1161
                Affiliations
                [1 ]Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
                [2 ]Baylor Institute for Immunology Research, Baylor Research Institute 3434 Live Oak St, Dallas, TX 75204, USA.
                [3 ]Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
                [4 ]Institute of Biophysics, Chinese Academy of Science, Beijing, China.
                [5 ]Department of Chemistry, University of California, Riverside, CA 92521, USA.
                Author notes
                [6]

                These authors contributed equally to this work.

                Correspondence should be addressed to G.C. ( gcheng@ 123456mednet.ucla.edu ) or Y.L. ( yongjun.liu@ 123456baylorhealth.com ).
                Article
                Manuscript ID: NIHMS410677
                DOI: 10.1038/ni.2460
                PMC ID: 3501571
                PubMed ID: 23142775
                SO-VID: 485b16c0-f84e-458f-9728-fcddde686f7c
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: T32 AR058921 || AR
                Categories
                Subject: Article

                ScienceOpen disciplines: Immunology
                Data availability:
                ScienceOpen disciplines: Immunology

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