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Differential regulation of type I interferon and epidermal growth factor pathways by a human Respirovirus virulence factor.

Abstract : A number of paramyxoviruses are responsible for acute respiratory infections in children, elderly and immuno-compromised individuals, resulting in airway inflammation and exacerbation of chronic diseases like asthma. To understand the molecular pathogenesis of these infections, we searched for cellular targets of the virulence protein C of human parainfluenza virus type 3 (hPIV3-C). We found that hPIV3-C interacts directly through its C-terminal domain with STAT1 and GRB2, whereas C proteins from measles or Nipah viruses failed to do so. Binding to STAT1 explains the previously reported capacity of hPIV3-C to block type I interferon signaling, but the interaction with GRB2 was unexpected. This adaptor protein bridges Epidermal Growth Factor (EGF) receptor to MAPK/ERK pathway, a signaling cascade recently found to be involved in airway inflammatory response. We report that either hPIV3 infection or transient expression of hPIV3-C both increase cellular response to EGF, as assessed by Elk1 transactivation and phosphorylation levels of ERK1/2, 40S ribosomal subunit protein S6 and translation initiation factor 4E (eIF4E). Furthermore, inhibition of MAPK/ERK pathway with U0126 prevented viral protein expression in infected cells. Altogether, our data provide molecular basis to explain the role of hPIV3-C as a virulence factor and determinant of pathogenesis and demonstrate that Paramyxoviridae have evolved a single virulence factor to block type I interferon signaling and to boost simultaneous cellular response to growth factors.
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Submitted on : Thursday, February 11, 2010 - 11:30:31 AM
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Grégory Caignard, Anastassia V. Komarova, Mehdi Bouraï, Thomas Mourez, Yves Jacob, et al.. Differential regulation of type I interferon and epidermal growth factor pathways by a human Respirovirus virulence factor.. PLoS Pathogens, Public Library of Science, 2009, 5 (9), pp.e1000587. ⟨10.1371/journal.ppat.1000587⟩. ⟨pasteur-00455180⟩

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