The Cellular RNA Helicase UAP56 Is Required for Prevention of Double-Stranded RNA Formation during Influenza A Virus Infection

Wisskirchen, Christian; Ludersdorfer, Thomas H.; Müller, Dominik A.; Moritz, Eva; Pavlovic, Jovan

doi:10.1128/jvi.02559-10

Cited by 60 publications

(67 citation statements)

References 44 publications

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“…It is possible that mouse Mx1 needs another cellular factor that is present only in the nucleus or that it is posttranslationally modified by a nuclear protein. For example, the RNA helicase UAP56 (or URH49) might act as a bridging protein, as it interacts with NP and with mouse Mx1 and human MxA (97,98). However, this helicase is not restricted to the nucleus and partially redistributes to the cytoplasm in the presence of human MxA (98), which argues against the hypothesis that it could be responsible for the strict nuclear activity of the mouse Mx1 protein.…”

Section: Antiviral Activity Against Orthomyxoviridaementioning

confidence: 43%

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Verhelst

Hulpiau

Saelens

2013

Microbiol Mol Biol Rev

255

178

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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.

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Section: Antiviral Activity Against Orthomyxoviridaementioning

confidence: 43%

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Verhelst

Hulpiau

Saelens

2013

Microbiol Mol Biol Rev

255

178

View full text Add to dashboard Cite

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“…Multiple cellular proteins interact with PB2 and/or NP and might fulfill this function. One of these proteins is the RNA helicase, UAP56, which interacts with NP and with Mx1 (50,51). We investigated the involvement of this helicase in the effect of Mx1 on the PB2-NP interaction.…”

Section: Discussionmentioning

confidence: 99%

Interferon-Inducible Protein Mx1 Inhibits Influenza Virus by Interfering with Functional Viral Ribonucleoprotein Complex Assembly

Verhelst

Parthoens

Schepens

et al. 2012

J Virol

197

168

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bMx1 is a GTPase that is part of the antiviral response induced by type I and type III interferons in the infected host. It inhibits influenza virus infection by blocking viral transcription and replication, but the molecular mechanism is not known. Polymerase basic protein 2 (PB2) and nucleoprotein (NP) were suggested to be the possible target of Mx1, but a direct interaction between Mx1 and any of the viral proteins has not been reported. We investigated the interplay between Mx1, NP, and PB2 to identify the mechanism of Mx1's antiviral activity. We found that Mx1 inhibits the PB2-NP interaction, and the strength of this inhibition correlated with a decrease in viral polymerase activity. Inhibition of the PB2-NP interaction is an active process requiring enzymatically active Mx1. We also demonstrate that Mx1 interacts with the viral proteins NP and PB2, which indicates that Mx1 protein has a direct effect on the viral ribonucleoprotein complex. In a minireplicon system, avian-like NP from swine virus isolates was more sensitive to inhibition by murine Mx1 than NP from human influenza A virus isolates. Likewise, murine Mx1 displaced avian NP from the viral ribonucleoprotein complex more easily than human NP. The stronger resistance of the A/H1N1 pandemic 2009 virus against Mx1 also correlated with reduced inhibition of the PB2-NP interaction. Our findings support a model in which Mx1 interacts with the influenza ribonucleoprotein complex and interferes with its assembly by disturbing the PB2-NP interaction.

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“…We have shown recently that MxA binds to UAP56, a DEAD-box helicase. UAP56 is also an interaction partner of NP and is required for efficient replication of IAV and evasion of the IFN response (22)(23)(24). Therefore, UAP56 may recruit MxA and NP to form a complex involving all three proteins.…”

mentioning

confidence: 99%

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

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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...

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The Cellular RNA Helicase UAP56 Is Required for Prevention of Double-Stranded RNA Formation during Influenza A Virus Infection

Cited by 60 publications

References 44 publications

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Interferon-Inducible Protein Mx1 Inhibits Influenza Virus by Interfering with Functional Viral Ribonucleoprotein Complex Assembly

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

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