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Interferon-induced antiviral protein MxA interacts with the cellular RNA helicases UAP56 and URH49


Wisskirchen, C; Ludersdorfer, T H; Müller, D A; Moritz, E; Pavlovic, J (2011). Interferon-induced antiviral protein MxA interacts with the cellular RNA helicases UAP56 and URH49. Journal of Biological Chemistry, 286(40):34743-34751.

Abstract

Mx proteins are a family of large GTPases that are induced
exclusively by interferon-alpha/beta and have a broad antiviral activity against several viruses, including influenza A virus (IAV). Although the antiviral activities of mouse Mx1 and human MxA have been studied extensively, the molecular mechanism of action remains largely unsolved. Because no direct interaction between Mx proteins and IAV proteins or RNA had been demonstrated so far, we addressed the question of whether Mx protein would interact with cellular proteins required for efficient replication of IAV. Immunoprecipitation of MxA revealed its association with two closely related RNA helicases, UAP56 and URH49.UAP56 and its paralog URH49 play an important role in
IAV replication and are involved in nuclear export of IAV
mRNAs and prevention of dsRNA accumulation in infected
cells. In vitro binding assays with purified recombinant proteins revealed that MxA formed a direct complex with the RNA helicases.
In addition, recombinant mouse Mx1 was also able to bind
to UAP56 or URH49. Furthermore, the complex formation
between cytoplasmic MxA and UAP56 or URH49 occurred in
the perinuclear region, whereas nuclear Mx1 interacted with
UAP56 or URH49 in distinct dots in the nucleus. Taken
together, our data reveal that Mx proteins exerting antiviral activity can directly bind to the two cellular DExD/H box RNA helicases UAP56 and URH49. Moreover, the observed subcellular localization of the Mx-RNA helicase complexes coincides with the subcellular localization, where human MxA and mouse Mx1 proteins act antivirally. On the basis of these data, we propose that Mx proteins exert their antiviral activity against IAV by interfering with the function of the RNA helicases UAP56 and URH49.

Mx proteins are a family of large GTPases that are induced
exclusively by interferon-alpha/beta and have a broad antiviral activity against several viruses, including influenza A virus (IAV). Although the antiviral activities of mouse Mx1 and human MxA have been studied extensively, the molecular mechanism of action remains largely unsolved. Because no direct interaction between Mx proteins and IAV proteins or RNA had been demonstrated so far, we addressed the question of whether Mx protein would interact with cellular proteins required for efficient replication of IAV. Immunoprecipitation of MxA revealed its association with two closely related RNA helicases, UAP56 and URH49.UAP56 and its paralog URH49 play an important role in
IAV replication and are involved in nuclear export of IAV
mRNAs and prevention of dsRNA accumulation in infected
cells. In vitro binding assays with purified recombinant proteins revealed that MxA formed a direct complex with the RNA helicases.
In addition, recombinant mouse Mx1 was also able to bind
to UAP56 or URH49. Furthermore, the complex formation
between cytoplasmic MxA and UAP56 or URH49 occurred in
the perinuclear region, whereas nuclear Mx1 interacted with
UAP56 or URH49 in distinct dots in the nucleus. Taken
together, our data reveal that Mx proteins exerting antiviral activity can directly bind to the two cellular DExD/H box RNA helicases UAP56 and URH49. Moreover, the observed subcellular localization of the Mx-RNA helicase complexes coincides with the subcellular localization, where human MxA and mouse Mx1 proteins act antivirally. On the basis of these data, we propose that Mx proteins exert their antiviral activity against IAV by interfering with the function of the RNA helicases UAP56 and URH49.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Virology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:7 October 2011
Deposited On:05 Mar 2012 13:30
Last Modified:05 Apr 2016 15:39
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Funders:Swiss National Science Foundation, Forschungskredit from the University of Zurich.
Additional Information:This research was originally published in Wisskirchen, C; Ludersdorfer, T H; Müller, D A; Moritz, E; Pavlovic, J (2011). Interferon-induced antiviral protein MxA interacts with the cellular RNA helicases UAP56 and URH49. Journal of Biological Chemistry, 286(40):34743-34751. © the American Society for Biochemistry and Molecular Biology.
Publisher DOI:10.1074/jbc.M111.251843
PubMed ID:21859714
Permanent URL: http://doi.org/10.5167/uzh-59702

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