Differential Regulation of Type I Interferon and Epidermal Growth Factor Pathways by a Human Respirovirus Virulence Factor

Grégory Caignard,Astrid Vabret,Frédéric Tangy,Mehdi Bouraï,Thomas Mourez,Pierre-Olivier Vidalain,Louis M Jones,François Freymuth,Yves Jacob,Flore Rozenberg,Anastassia V Komarova

doi:10.1371/journal.ppat.1000587

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.

Highlights

Viruses need to interact with host macromolecules to hijack the cellular machinery and replicate
To provide molecular basis to this activity, we found that the C protein of human parainfluenza virus type 3, the most frequent human Respirovirus, interacts with STAT1, a key component of type I interferon receptor complex
HPIV3-C was found to interact with GRB2, an adaptor molecule involved in cellular response to Epidermal Growth Factor (EGF), and to enhance cell response to this cytokine

Summary

Introduction

Viruses need to interact with host macromolecules to hijack the cellular machinery and replicate. Specific viral factors stimulate survival pathways to prevent apoptosis of infected cells or inhibit cell signaling involved in immune response. Among these pathways, IFN-a/b signaling represents a prime target for viruses because of its critical role in the induction of both innate and adaptive antiviral immune responses [1]. IFN-a/b transduce signals through direct binding to a cell surface receptor composed of two transmembrane subunits, IFNAR1 and IFNAR2c [2]. This interaction activates IFNAR1/IFNAR2c associated kinases Tyk and Jak that subsequently phosphorylate STAT2 and STAT1 transcription factors. Most viruses that are pathogenic in vertebrates have evolved virulence factors both to block IFN-a/b expression and signal transduction downstream of IFN-a/b receptor

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Conclusion