Detection of new biallelic polymorphisms in the human MxA gene

Duc, Tam Tran Thi; Farnir, Frédéric; Michaux, Charles; Desmecht, Daniël; Cornet, A

doi:10.1007/s11033-012-1708-7

Cited by 9 publications

(15 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a recent publication studying the GTPase mechanism of MxA and its role for MxA antiviral function (9), we have already characterized two of these variants located in the G domain, G255E and V268M. They were previously identified by Duc and colleagues (25) studying polymorphisms in the MX1 gene in a small group of 267 healthy individuals (Table 1). These two variants were also found in the ExAC database and were included in the present study for further characterization.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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

Graf

Dick

Sendker

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

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.http://www.jbc.org/cgi

show abstract

Section: Resultsmentioning

confidence: 99%

“…The two examined variations were detected in a small sequencing study of the human MX1 gene (25) and are located in the G interface of MxA. We showed that the variations interfered with G domain dimerization and consequently GTPase activity resulting in the reduction or even the complete loss of antiviral activity (9).…”

mentioning

confidence: 90%

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

Graf

Dick

Sendker

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…A Western blot showing detection of Mx1 expression in lysates of transfected cells from one of three experiments is shown. reduced antiviral activity as a result of decreased GTPase activity (40,41). Comparison of the G interface of SMx1 and A2G Mx1 revealed 5 differences (at positions 152, 227, 230, 231, and 236) which might influence antiviral activity through an altered dimerization at the G interface.…”

Section: Discussionmentioning

confidence: 98%

Functional Comparison of Mx1 from Two Different Mouse Species Reveals the Involvement of Loop L4 in the Antiviral Activity against Influenza A Viruses

Verhelst

Spitaels

Nürnberger

et al. 2015

J Virol

View full text Add to dashboard Cite

The interferon-induced Mx1 gene is an important part of the mammalian defense against influenza viruses. Mus musculus Mx1 inhibits influenza A virus replication and transcription by suppressing the polymerase activity of viral ribonucleoproteins (vRNPs). Here, we compared the anti-influenza virus activity of Mx1 from Mus musculus A2G with that of its ortholog from Mus spretus. We found that the antiviral activity of M. spretus Mx1 was less potent than that of M. musculus Mx1. Comparison of the M. musculus Mx1 sequence with the M. spretus Mx1 sequence revealed 25 amino acid differences, over half of which were present in the GTPase domain and 2 of which were present in loop L4. However, the in vitro GTPase activity of Mx1 from the two mouse species was similar. Replacement of one of the residues in loop L4 in M. spretus Mx1 by the corresponding residue of A2G Mx1 increased its antiviral activity. We also show that deletion of loop L4 prevented the binding of Mx1 to influenza A virus nucleoprotein and, hence, abolished the antiviral activity of mouse Mx1. These results indicate that loop L4 of mouse Mx1 is a determinant of antiviral activity. Our findings suggest that Mx proteins from different mammals use a common mechanism to inhibit influenza A viruses. IMPORTANCEMx proteins are evolutionarily conserved in vertebrates and inhibit a wide range of viruses. Still, the exact details of their antiviral mechanisms remain largely unknown. Functional comparison of the Mx genes from two species that diverged relatively recently in evolution can provide novel insights into these mechanisms. We show that both Mus musculus A2G Mx1 and Mus spretus Mx1 target the influenza virus nucleoprotein. We also found that loop L4 in mouse Mx1 is crucial for its antiviral activity, as was recently reported for primate MxA. This indicates that human and mouse Mx proteins, which have diverged by 75 million years of evolution, recognize and inhibit influenza A viruses by a common mechanism.T he Mx proteins are interferon (IFN)-induced GTPases that inhibit a wide range of viruses, including Orthomyxoviridae, Bunyaviridae, and Rhabdoviridae (reviewed in references 1 and 2). The gene encoding mouse Mx1, the founder member of this family of antiviral proteins, was discovered almost 30 years ago on the basis of the resistance of the A2G mouse strain to influenza A virus infection (3, 4). This resistance is inherited as a dominant autosomal trait and depends on a single gene (Mx1) located on chromosome 16 (5). However, most inbred laboratory mouse strains contain a three-exon deletion or a nonsense mutation in the Mx1 locus and are susceptible to influenza viruses (6). In contrast, Mx1 ϩ and Mx1 Ϫ alleles can be found at similar frequencies in wild mice. This suggests that there is a selective advantage of heterozygosity at the Mx1 locus, as one would expect that the Mx1 ϩ allele would otherwise be fixed in wild mouse strains (7). The mouse Mx locus contains Mx1 and Mx2. Remarkably, Mx2 is also nonfunctional in laboratory mouse strains ...

show abstract

“…However, a recent study analyzing variations in the MxA genes of 267 healthy individuals identified two rare nucleotide changes that result in amino acid exchanges at positions 255 and 268 (50). Based on the structural models of the G domain dimer, these exchanges localize to the G interface and might thus influence its formation or function.…”

Section: Discussionmentioning

confidence: 99%

“…Two of them are located in the G interface and lead to an exchange of glycine to glutamic acid at position 255 and valine to methionine at position 268, respectively (Fig. 10A) (50). We tested whether these mutations affect catalysis and function of MxA.…”

Section: Role Of Nucleotide Binding and Hydrolysis In Formation Of Cymentioning

confidence: 99%

Role of Nucleotide Binding and GTPase Domain Dimerization in Dynamin-like Myxovirus Resistance Protein A for GTPase Activation and Antiviral Activity

Dick

Graf

Olal

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Human myxovirus resistance protein A (MxA) is an antiviral dynamin-related GTPase. Results: Dimerization of MxA via a GTPase domain interface is required for GTP hydrolysis and antiviral activity. Conclusion: GTP binding allows GTPase domain dimerization and membrane-associated assembly of MxA, but it is not sufficient to induce a sustained antiviral effect. Significance: New mechanistic insights into the antiviral action of MxA are provided.

show abstract

Detection of new biallelic polymorphisms in the human MxA gene

Cited by 9 publications

References 21 publications

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

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

Functional Comparison of Mx1 from Two Different Mouse Species Reveals the Involvement of Loop L4 in the Antiviral Activity against Influenza A Viruses

Role of Nucleotide Binding and GTPase Domain Dimerization in Dynamin-like Myxovirus Resistance Protein A for GTPase Activation and Antiviral Activity

Contact Info

Product

Resources

About