Open AccessViperin is an iron‐sulfur protein that inhibits genome synthesis of tick‐borne encephalitis virus via radical SAM domain activity
Author(s) -
Upadhyay Arunkumar S.,
Vonderstein Kirstin,
Pichlmair Andreas,
Stehling Oliver,
Bennett Keiryn L.,
Dobler Gerhard,
Guo JuTao,
SupertiFurga Giulio,
Lill Roland,
Överby Anna K.,
Weber Friedemann
Publication year - 2014
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/cmi.12241
Subject(s) - biology , antiviral protein , rna , mutant , tick borne encephalitis virus , genome , virus , virology , interferon , intracellular , microbiology and biotechnology , biochemistry , gene , encephalitis
Summary 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 [4 Fe ‐4 S ] 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 55 Fe , 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 55 Fe . Mutants lacking the extreme C ‐terminal W 361 did not interact with CIAO1 , were not matured, and were antivirally inactive. Moreover, intracellular removal of SAM by ectopic expression of the bacteriophage T 3 SAM ase abolished antiviral activity. Collectively, our data suggest that viperin requires CIAO1 for [4 Fe ‐4 S ] cluster assembly, and acts through an enzymatic, Fe ‐ S cluster‐ and SAM ‐dependent mechanism to inhibit viral RNA synthesis.