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Viperin is an iron‐sulfur protein that inhibits genome synthesis of tick‐borne encephalitis virus via radical SAM domain activity
Authors:Andreas Pichlmair  Oliver Stehling  Keiryn L Bennett  Gerhard Dobler  Ju‐Tao Guo  Giulio Superti‐Furga  Roland Lill  Friedemann Weber
Institution:1. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, , Vienna, Austria;2. Innate Immunity Laboratory, Max‐Planck Institute of Biochemistry, , Martinsried/Munich, Germany;3. Institute for Cytobiology and Cytopathology, Philipps‐University Marburg, , D‐35032 Marburg, Germany;4. Bundeswehr Institute of Microbiology, , D‐80937 Munich, Germany;5. Department of Microbiology and Immunology, Drexel University College of Medicine, , Doylestown, PA, 18902 USA;6. Max‐Planck‐Institut für terrestrische Mikrobiologie, , 35043 Marburg, Germany;7. LOEWE Zentrum für Synthetische Mikrobiologie SynMikro, , 35043 Marburg, Germany
Abstract:Viperin is an interferon‐induced protein with a broad antiviral activity. This evolutionary conserved protein contains a radical S‐adenosyl‐l ‐methionine (SAM) domain which has been shown in vitro to hold a 4Fe‐4S] cluster. We identified tick‐borne encephalitis virus (TBEV) as a novel target for which human viperin inhibits productionof the viral genome RNA. Wt viperin was found to require ER localization for full antiviral activity and to interact with the cytosolic Fe/S protein assembly factor CIAO1. Radiolabelling in vivo revealed incorporation of 55Fe, indicative for the presence of an Fe‐S cluster. Mutation of the cysteine residues ligating the Fe‐S cluster in the central radical SAM domain entirely abolished both antiviral activity and incorporation of 55Fe. Mutants lacking the extreme C‐terminal W361 did not interact with CIAO1, were not matured, and were antivirally inactive. Moreover, intracellular removal of SAM by ectopic expression of the bacteriophage T3 SAMase abolished antiviral activity. Collectively, our data suggest that viperin requires CIAO1 for 4Fe‐4S] cluster assembly, and acts through an enzymatic, Fe‐S cluster‐ and SAM‐dependent mechanism to inhibit viral RNA synthesis.
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