Journal article
Effects of allelic variations in the human myxovirus resistance protein A on its antiviral activity
The Journal of biological chemistry, v 293(9), pp 3056-3072
02 Mar 2018
PMID: 29330299
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Only a minority of patients infected with seasonal influenza A viruses exhibit 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 MxA's antiviral specificity. 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.
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Details
- Title
- Effects of allelic variations in the human myxovirus resistance protein A on its antiviral activity
- Creators
- Laura Graf - University of FreiburgAlexej Dick - Max Delbrück CenterFranziska Sendker - University of FreiburgEmanuel Barth - Friedrich Schiller University JenaManja Marz - Friedrich Schiller University JenaOliver Daumke - Max Delbrück CenterGeorg Kochs - University of Freiburg
- Publication Details
- The Journal of biological chemistry, v 293(9), pp 3056-3072
- Publisher
- Elsevier
- Grant note
- KO 1579/8-2 / Deutsche Forschungsgemeinschaft
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000426562800003
- Scopus ID
- 2-s2.0-85042942220
- Other Identifier
- 991021230004104721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology