Dataset Information

Molecular determinants for nuclear import of influenza A PB2 by importin ? isoforms 3 and 7.

ABSTRACT: Influenza A virus polymerase subunit PB2 is a major virulence determinant implicated in pathogenicity and host adaptation. During cross-species virus transfer from avian to mammalian cells, PB2 switches specificity from importin ?3 to ?7. This specificity is not recapitulated in vitro, where PB2 binds all importin ? isoforms with comparably high affinity. In this study, we investigated the structure, conformational dynamics, and autoinhibition of importin ? isoforms 1, 3, and 7 in complex with PB2. Our data suggest that association of PB2 with ?3 and ?7 is favored by reduced autoinhibition of these isoforms and by the unique structure of the nuclear localization signal (NLS) domain of PB2. We propose that by recruiting importin ?3 or ?7 in the absence of importin ?, PB2 reduces the complexity of adaptor-mediated import to a pseudo-bimolecular reaction, thereby acquiring a kinetic advantage over classical NLS cargos, which form an import complex only when importin ? and ? are simultaneously available.

SUBMITTER: Pumroy RA

PROVIDER: S-EPMC4346194 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Molecular determinants for nuclear import of influenza A PB2 by importin α isoforms 3 and 7.

Pumroy Ruth A RA Ke Song S Hart Darren J DJ Zachariae Ulrich U Cingolani Gino G

Structure (London, England : 1993) 20150115 2

Influenza A virus polymerase subunit PB2 is a major virulence determinant implicated in pathogenicity and host adaptation. During cross-species virus transfer from avian to mammalian cells, PB2 switches specificity from importin α3 to α7. This specificity is not recapitulated in vitro, where PB2 binds all importin α isoforms with comparably high affinity. In this study, we investigated the structure, conformational dynamics, and autoinhibition of importin α isoforms 1, 3, and 7 in complex with P ...[more]

PMID: 25599645

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Project description:Human adenoviruses (HAdV) are ubiquitous within the human population and comprise a significant burden of respiratory illnesses worldwide. Pediatric and immunocompromised individuals are at particular risk for developing severe disease; however, no approved antiviral therapies specific to HAdV exist. Ivermectin is an FDA-approved broad-spectrum antiparasitic drug that also exhibits antiviral properties against a diverse range of viruses. Its proposed function is inhibiting the classical protein nuclear import pathway mediated by importin-α (Imp-α) and -β1 (Imp-β1). Many viruses, including HAdV, rely on this host pathway for transport of viral proteins across the nuclear envelope. In this study, we show that ivermectin inhibits HAdV-C5 early gene transcription, early and late protein expression, genome replication, and production of infectious viral progeny. Similarly, ivermectin inhibits genome replication of HAdV-B3, a clinically important pathogen responsible for numerous recent outbreaks. Mechanistically, we show that ivermectin disrupts binding of the viral E1A protein to Imp-α without affecting the interaction between Imp-α and Imp-β1. Our results further extend ivermectin's broad antiviral activity and provide a mechanistic underpinning for its mode of action as an inhibitor of cellular Imp-α/β1-mediated nuclear import.IMPORTANCE Human adenoviruses (HAdVs) represent a ubiquitous and clinically important pathogen without an effective antiviral treatment. HAdV infections typically cause mild symptoms; however, individuals such as children, those with underlying conditions, and those with compromised immune systems can develop severe disseminated disease. Our results demonstrate that ivermectin, an FDA-approved antiparasitic agent, is effective at inhibiting replication of several HAdV types in vitro This is in agreement with the growing body of literature suggesting ivermectin has broad antiviral activity. This study expands our mechanistic knowledge of ivermectin by showing that ivermectin targets the ability of importin-α (Imp-α) to recognize nuclear localization sequences, without effecting the Imp-α/β1 interaction. These data also exemplify the applicability of targeting host factors upon which viruses rely as a viable antiviral strategy.

Dataset Information

Molecular determinants for nuclear import of influenza A PB2 by importin ? isoforms 3 and 7.

Publications

Molecular determinants for nuclear import of influenza A PB2 by importin α isoforms 3 and 7.

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