Oligomerization and GTP-binding requirements of MxA for viral target recognition and antiviral activity against influenza A virus [Microbiology]
October 27th, 2015 by Nigg, P. E., Pavlovic, J.
The interferon (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 GTPĪ³S, purified MxA disassembled into tetramers and dimers. Dimeric forms did not further disassemble into monomers. Infection experiments revealed that besides wild type MxA also dimeric and monomeric variants of MxA 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 weaker 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.