title: ArfGAP Domain-Containing Protein 2 (ADAP2) Integrates Upstream and Downstream Modules of RIG-I Signaling and Facilitates Type I Interferon Production.
abstract: Transcription of type I interferon genes during RNA virus infection requires signal communication between several pattern recognition receptor (PRR)-adaptor complexes located at distinct subcellular membranous compartments and a central cytoplasmic TBK1-interferon regulatory factor 3 (IRF3) kinase-transcription factor module. However, how the cell integrates signal transduction through spatially distinct modules of antiviral signaling pathways is less defined. RIG-I is a major cytosolic PRR involved in the control of several RNA viruses. Here we identify ArfGAP domain-containing protein 2 (ADAP2) as a key novel scaffolding protein that integrates different modules of the RIG-I pathway, located at distinct subcellular locations, and mediates cellular antiviral type I interferon production. ADAP2 served to bridge the mitochondrial membrane-bound upstream RIG-I adaptor MAVS and the downstream cytosolic complex of NEMO (regulatory subunit of TBK1), TBK1, and IRF3, leading to IRF3 phosphorylation. Furthermore, independently, ADAP2 also functioned as a major orchestrator of the interaction of TBK1 with NEMO and IRF3. Mutational andin vitrocell-free reconstituted RIG-I signaling assay-based analyses identified that the ArfGAP domain of ADAP2 mediates the interferon response. TRAF3 acted as a trigger for ADAP2 to recruit RIG-I pathway component proteins into a single macromolecular complex. This study provides important novel insights into the assembly and integration of different modules of antiviral signaling cascades.
authors.affiliation: Program on Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Bist
authors.affiliation: Program on Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Susana Soo-Yeon
authors.initials: SS
authors.lastname: Kim
authors.affiliation: Program on Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Niyas Kudukil
authors.initials: NK
authors.lastname: Pulloor
authors.affiliation: Program on Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Kathleen
authors.initials: K
authors.lastname: McCaffrey
authors.affiliation: Program on Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Sajith Kumar
authors.initials: SK
authors.lastname: Nair
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada.
authors.forename: Yiliu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada.
authors.forename: Rongtuan
authors.initials: R
authors.lastname: Lin
authors.affiliation: Program on Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore manoj.krishnan@duke-nus.edu.sg.
authors.forename: Manoj N
authors.initials: MN
authors.lastname: Krishnan
mesh_terms: D002474:Cell-Free System; D000071457:DEAD Box Protein 58 / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis* / Q000235:genetics; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D000072417:Protein Domains; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013347:Subcellular Fractions / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D018116:Vesiculovirus / Q000502:physiology
chemical_list: C470610:ADAP2 protein, human; D020690:GTPase-Activating Proteins; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D016328:NF-kappa B; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition; D011994:Recombinant Proteins; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58
keywords: RIG-I; innate immunity; interferons