ArfGAP domain-containing protein 2 (ADAP2) integrates upstream and downstream modules of RIG-I signaling and facilitates type I interferon production

Pradeep Bist, Susana Soo Yeon Kim, Niyas Kudukil Pulloor, Kathleen McCaffrey, Sajith Kumar Nair, Yiliu Liu, Rongtuan Lin, Manoj N. Krishnan

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5 Citations (Scopus)

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 and in vitro cell-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.

Original languageEnglish
Article numbere00537-16
Number of pages21
JournalMolecular and Cellular Biology
Volume37
Issue number6
DOIs
Publication statusPublished - 1 Jan 2017
Externally publishedYes

Keywords

  • Innate immunity
  • Interferons
  • RIG-I

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