Higher polymerase activity of a human influenza virus enhances activation of the hemagglutinin-induced Raf-MEK-ERK signal cascadeReportar como inadecuado




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Virology Journal

, 4:134

First Online: 05 December 2007Received: 15 November 2007Accepted: 05 December 2007

Abstract

Influenza viruses replicate within the nucleus of infected cells. Viral genomic RNA, three polymerase subunits PB2, PB1, and PA, and the nucleoprotein NP form ribonucleoprotein complexes RNPs that are exported from the nucleus late during the infectious cycle. The virus-induced Raf-MEK-ERK MAPK signal cascade is crucial for efficient virus replication. Blockade of this pathway retards RNP export and reduces virus titers. Hemagglutinin HA accumulation and its tight association with lipid rafts activate ERK and enhance localization of cytoplasmic RNPs. We studied the induction of MAPK signal cascade by two seasonal human influenza A viruses A-HK-218449-06 H3N2 and A-HK-218847-06 H1N1 that differed substantially in their replication efficiency in tissue culture. Infection with H3N2 virus, which replicates efficiently, resulted in higher HA expression and its accumulation on the cell membrane, leading to substantially increased activation of MAPK signaling compared to that caused by H1N1 subtype. More H3N2-HAs were expressed and accumulated on the cell membrane than did H1N1-HAs. Viral polymerase genes, particularly H3N2-PB1 and H3N2-PB2, were observed to contribute to increased viral polymerase activity. Applying plasmid-based reverse genetics to analyze the role of PB1 protein in activating HA-induced MAPK cascade showed that recombinant H1N1 virus possessing the H3N2-PB1 rgH1N1-H3N2-PB1 induced greater ERK activation, resulting in increased nuclear export of the viral genome and higr virus titers. We conclude that enhanced viral polymerase activity promotes the replication and transcription of viral RNA leading to increased accumulation of HA on the cell surface and thereby resulting in an upregulation of the MAPK cascade and more efficient nuclear RNP-export as well as virus production.

Electronic supplementary materialThe online version of this article doi:10.1186-1743-422X-4-134 contains supplementary material, which is available to authorized users.

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Autor: Henju Marjuki - Hui-Ling Yen - John Franks - Robert G Webster - Stephan Pleschka - Erich Hoffmann

Fuente: https://link.springer.com/



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