Pandemic Influenza A Viruses Escape from Restriction by Human MxA through Adaptive Mutations in the Nucleoprotein

Mänz, Benjamin; Dornfeld, Dominik; Götz, Veronika; Zell, Roland; Zimmermann, Petra; Haller, Otto; Kochs, Georg; Schwemmle, Martin

doi:10.1371/journal.ppat.1003279

Cited by 178 publications

(325 citation statements)

References 65 publications

Supporting

Mentioning

314

Contrasting

Unclassified

Order By: Relevance

“…5). These residues are solvent exposed and therefore readily accessible for cellular factors, such as the Mx1 protein (95). We recently demonstrated that Mx1 interacts with both the NP and PB2 proteins and disturbs their interaction by a mechanism that depends on GTP binding and/or GTPase activity.…”

Section: Antiviral Activity Against Orthomyxoviridaementioning

confidence: 99%

See 1 more Smart Citation

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Verhelst

Hulpiau

Saelens

2013

Microbiol Mol Biol Rev

266

178

View full text Add to dashboard Cite

SUMMARY Fifty years after the discovery of the mouse Mx1 gene, researchers are still trying to understand the molecular details of the antiviral mechanisms mediated by Mx proteins. Mx proteins are evolutionarily conserved dynamin-like large GTPases, and GTPase activity is required for their antiviral activity. The expression of Mx genes is controlled by type I and type III interferons. A phylogenetic analysis revealed that Mx genes are present in almost all vertebrates, usually in one to three copies. Mx proteins are best known for inhibiting negative-stranded RNA viruses, but they also inhibit other virus families. Recent structural analyses provide hints about the antiviral mechanisms of Mx proteins, but it is not known how they can suppress such a wide variety of viruses lacking an obvious common molecular pattern. Perhaps they interact with a (partially) symmetrical invading oligomeric structure, such as a viral ribonucleoprotein complex. Such an interaction may be of a fairly low affinity, in line with the broad target specificity of Mx proteins, yet it would be strong enough to instigate Mx oligomerization and ring assembly. Such a model is compatible with the broad “substrate” specificity of Mx proteins: depending on the size of the invading viral ribonucleoprotein complexes that need to be wrapped, the assembly process would consume the necessary amount of Mx precursor molecules. These Mx ring structures might then act as energy-consuming wrenches to disassemble the viral target structure.

show abstract

Section: Antiviral Activity Against Orthomyxoviridaementioning

confidence: 99%

“…This nonhydrolyzable GTP analog pre- The residues important for Mx1 and MxA resistance are highlighted in red. Residues that contribute in only a minor way to Mx1 resistance are indicated in light red (95). Right, these important residues are also exposed on the surface of viral ribonucleoprotein (RNP) complexes (PDB file 4BBL [146]).…”

Section: Thovmentioning

confidence: 99%

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Verhelst

Hulpiau

Saelens

2013

Microbiol Mol Biol Rev

266

178

View full text Add to dashboard Cite

show abstract

“…Interestingly, these twoIAVstrainsdevelopedtheirMxAresistancephenotypeindependently of each other (19) and, therefore, introduced distinct adaptive mutations into their NP coding sequence. These findings led us to the conclusion that there are at least two mechanisms for IAV to evade restriction by MxA.…”

Section: Discussionmentioning

confidence: 99%

“…Dimeric Variants of MxA Interact with NP Independent of Other Viral Proteins-Despite the fact that, so far, experimental evidence for a physical interaction of human MxA with NP is lacking, the available data strongly suggest a functional relationship between these two proteins (18,19,33) (Fig. 5B).…”

Section: Mxa Inhibits Iav Replication At Amentioning

confidence: 99%

See 1 more Smart Citation

Oligomerization and GTP-binding Requirements of MxA for Viral Target Recognition and Antiviral Activity against Influenza A Virus

Nigg

Pavlovic

2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

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.The interferon system plays a pivotal role in the defense against viral infection. Interferons type I and III induce the expression of more than 300 proteins, many of them exhibiting intrinsic antiviral activity (1-3). The human myxovirus resistance protein A (MxA) 3 protein is induced exclusively by type I and type III interferons and restricts the replication of a large variety of RNA and DNA viruses (reviewed in Ref. 4). Mx proteins are members of the dynamin superfamily of large GTPases. They contain an amino-terminal globular GTPase (G) domain and a carboxy-terminal stalk domain (5, 6). The stalk domain harbors the GTPase effector domain and additional structural elements, including the L4 loop required for antiviral activity and target specificity (7-9). The G and stalk domains are connected via the bundle signaling element (BSE), which strongly resembles the BSE responsible for intramolecular signaling in dynamin (10). Mx proteins exhibit a high intrinsic rate of GTP hydrolysis, although the affinity to GTP is weak (11). Moreover, the human MxA protein forms dimers and tetramers and has the capacity to form higher oligomeric ringlike structures through a series of intra-and intermolecular interactions (5, 6, 12, 13). Introduction of mutations into the interfaces of the intermolecular interaction sites or hinge regions of MxA prevents assembly into higher-order multimeric forms. These mutations lead to the formation of MxA into tetramers, dimers, and monomers (5, 12).So far, little is known about the molecular mechanism of action of the human MxA...

show abstract

Mx genes: host determinants controlling influenza virus infection and trans-species transmission

Haller

Kochs

2019

Hum Genet

Self Cite

View full text Add to dashboard Cite

The human MxA protein, encoded by the interferon-inducible MX1 gene, is an intracellular influenza A virus (IAV) restriction factor. It can protect transgenic mice from severe IAV-induced disease, indicating a key role of human MxA for host survival and suggesting that natural variations in MX1 may account for inter-individual differences in disease severity among humans. MxA also provides a robust barrier against zoonotic transmissions of avian and swine IAV strains. Therefore, zoonotic IAV must acquire MxA escape mutations to achieve sustained human-to-human transmission. Here, we discuss recent progress in the field.

show abstract

Pandemic Influenza A Viruses Escape from Restriction by Human MxA through Adaptive Mutations in the Nucleoprotein

Cited by 178 publications

References 65 publications

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Oligomerization and GTP-binding Requirements of MxA for Viral Target Recognition and Antiviral Activity against Influenza A Virus

Mx genes: host determinants controlling influenza virus infection and trans-species transmission

Contact Info

Product

Resources

About