Oligomerization and GTP-binding Requirements of MxA for Viral Target Recognition and Antiviral Activity against Influenza A Virus.
The IFN-induced human myxovirus resistance protein A (MxA) exhibits a broad antiviral activity against many viruses, including influenza A virus (IAV). MxA belongs to the family of dynamin-like GTPases and assembles in vitro into dimers, tetramers, and oligomeric ring-like structures. The molecular mechanism of action remains to be elucidated. Furthermore, it is not clear whether MxA exerts its antiviral activity in a monomeric and/or multimeric form. Using a set of MxA mutants that form complexes with defined stoichiometry, we observed that, in the presence of guanosine 5'-O-(thiotriphosphate), purified MxA disassembled into tetramers and dimers. Dimeric forms did not further disassemble into monomers. Infection experiments revealed that besides wild-type MxA, dimeric and monomeric variants of MxA also efficiently restricted IAV at a replication step after primary transcription. Moreover, only dimeric MxA was able to form stable complexes with the nucleoprotein (NP) of IAV. MxA interacted with NP independently of other viral components. Interestingly, the dimeric form of MxA was able to efficiently bind to NP from several MxA-sensitive strains but interacted much more weakly with NP from the MxA-resistant PR8 strain derived from the H1N1 1918 lineage. Taken together, these data suggest that, during infection, a fraction of MxA disassembles into dimers that bind to NP synthesized following primary transcription in the cytoplasm, thereby preventing viral replication.
From the Institute of Medical Virology, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
Patricia E
PE
Nigg
From the Institute of Medical Virology, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland pavlovic.jovan@virology.uzh.ch.
Jovan
J
Pavlovic
D000818:Animals; D001704:Biopolymers / Q000378:metabolism*; D002460:Cell Line; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D009980:Influenza A virus / Q000378:metabolism*; D064547:Myxovirus Resistance Proteins / Q000378:metabolism*
D001704:Biopolymers; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D006160:Guanosine Triphosphate
GTPase; Mx protein; antiviral agent; influenza virus; innate immunity; interferon; nucleoprotein; protein assembly