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Effects of allelic variations in the human myxovirus resistance protein A on its antiviral activity

Item Type:Article
Title:Effects of allelic variations in the human myxovirus resistance protein A on its antiviral activity
Creators Name:Graf, L. and Dick, A. and Sendker, F. and Barth, E. and Marz, M. and Daumke, O. and Kochs, G.
Abstract:Only a minority of patients infected with seasonal influenza A viruses exhibits a severe or fatal outcome of infection, but the reasons for this inter-individual variability in influenza susceptibility are unclear. To gain further insights into the molecular mechanisms underlying this variability, we investigated naturally occurring allelic variations of the myxovirus resistance 1 (MX1) gene coding for the influenza restriction factor MxA. The interferon-induced dynamin-like GTPase consists of an N-terminal GTPase domain, a bundle signaling element, and a C-terminal stalk responsible for oligomerization and viral target recognition. We used online databases to search for variations in the MX1 gene. Deploying in vitro approaches, we found that non-synonymous variations in the GTPase domain cause the loss of antiviral and enzymatic activities. Furthermore, we showed that these amino acid substitutions disrupt the interface for GTPase domain dimerization required for the stimulation of GTP hydrolysis. Variations in the stalk were neutral or slightly enhanced or abolished MxA antiviral function. Remarkably, two other stalk variants altered the antiviral specificity of MxA. Variations causing the loss of antiviral activity were found only in heterozygous carriers. Interestingly, the inactive stalk variants blocked the antiviral activity of wt MxA in a dominant-negative way suggesting that heterozygotes are phenotypically MxA-negative. In contrast, the GTPase-deficient variants showed no dominant-negative effect, indicating that heterozygous carriers should remain unaffected. Our results demonstrate that naturally occurring mutations in the human MX1 gene can influence MxA function which may explain individual variations in influenza virus susceptibility in the human population.
Keywords:Dynamin, Genetic Polymorphism, Influenza Virus, Innate Immunity, Interferon, Mx Proteins, Allelic Variations, Antiviral Response
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:293
Number:9
Page Range:3056-3072
Date:2 March 2018
Official Publication:https://doi.org/10.1074/jbc.M117.812784
PubMed:View item in PubMed

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