A Small GTPase Regulates the Influenza Virus Neuraminidase Transport and Viral Replication

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Updatetime:2012-04-11
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Neuraminidase (NA), a single-pass type II membrane protein and existing as a homotetramer, can specifically remove the terminal sialic acid residues from viral and cellular glycoconjugates. It is described as a receptor-destroying enzyme that facilitates virus release and efficiently spreads the progeny virus from cell to cell. Moreover, NA plays a role in the determination of host range restriction and virulence of influenza virus. Based on its characteristics, NA has been the preferable target of anti-influenza drugs. However, little is known about the mechanisms and host factors that are involved in regulating the intracellular and cell surface transport of NA.

To address this issue, team led by Prof. CHEN Jilong in Institute of Microbiology, Chinese Academy of Sciences examined the gene expression profile ofhost cells infected with influenza A virus using cDNA microarray analysis. They found that the Cdc42-specific GAP, ARHGAP21 differentially expressed in infected and non-infected host cells. The Cdc42 is a small GTPase involved in regulating actin dynamics. Interestingly, they observed that expression of active or inactive forms of Cdc42 or depletion of its GAP significantly affected the transport of NA to the host cell surface. Consistent with these data, experiments using Cdc42-knockdown cells and cells overexpressing ARHGAP21 demonstrated that Cdc42 activity is important for the transport of NA to the plasma membrances. In addition, they revealed that both Cdc42 and ARHGAP21 impact virus replication. What's more, the researchers have also found there exists a population of T cells that is susceptible to influenza A virus infection and the Itk/PLC-γ1 signaling is required for efficient replication of influenza virus in infected lymphocytes.

These results reveal host factors small GTPase Cdc42 and ARHGAP21 are involved in regulating NA transport to the cell surface, and illustrate that Itk signaling pathway in host cells plays an important role in influenza virus infection and replication. These findings are critical for better understanding of influenza virus life cycle and pathogenesis, and contribute to clarifying the regulation network in influenza virus infection and replication. In addition, these studies are likely to extend our current design of virus-targeted drugs in the battle against the recurring threat of seasonal and pandemic influenza virus infections.

The studies have been published in The Journal of Biological Chemistry and Journal of General Virology. The links are as follows, http://www.jbc.org/content/287/13/9804.long, http://vir.sgmjournals.org/content/early/2012/01/26/vir.0.041228-0 .

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