Header

UZH-Logo

Maintenance Infos

Oligomerization and GTP-binding requirements of MxA for viral target recognition and antiviral activity against influenza a virus


Nigg, Patricia E; Pavlovic, Jovan (2015). Oligomerization and GTP-binding requirements of MxA for viral target recognition and antiviral activity against influenza a virus. Journal of Biological Chemistry, 290(50):29893-29906.

Abstract

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.

Abstract

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.

Statistics

Citations

13 citations in Web of Science®
12 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

26 downloads since deposited on 19 Jan 2016
17 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Virology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:11 December 2015
Deposited On:19 Jan 2016 11:08
Last Modified:08 Dec 2017 17:44
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Funders:Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Grant 31003A_143834
Additional Information:This research was originally published in The Journal of Biological Chemistry. Nigg, Pavlovic.Oligomerization and GTP-binding Requirements of MxA for Viral Target Recognition and Antiviral Activity against Influenza A Virus. The Journal of Biological Chemistry. 2015; 290, 29893-29906 © the American Society for Biochemistry and Molecular Biology.
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1074/jbc.M115.681494
PubMed ID:26507657

Download

Download PDF  'Oligomerization and GTP-binding requirements of MxA for viral target recognition and antiviral activity against influenza a virus'.
Preview
Content: Accepted Version
Language: English
Filetype: PDF
Size: 3MB
View at publisher
Download PDF  'Oligomerization and GTP-binding requirements of MxA for viral target recognition and antiviral activity against influenza a virus'.
Preview
Content: Published Version
Filetype: PDF
Size: 3MB