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

PLoS Pathogens

Flore Rozenberg¹  Yves Jacob²  Grégory Caignard³  Mehdi Bouraï³  Anastassia V. Komarova³  Pierre-Olivier Vidalain³  Thomas Mourez³  François Freymuth⁴  Frédéric Tangy⁴  Astrid Vabret⁵  Louis M. Jones⁶ 

[1] Groupe Logiciels et Banques de Données, Institut Pasteur, Paris, France;Laboratoire de Bactériologie-Virologie, Hôpital Lariboisière-APHP, Paris, France;Laboratoire de Génomique Virale et Vaccination, Department of Virology, Institut Pasteur, CNRS URA 3015, Paris, France;Laboratoire de Virologie Humaine et Moléculaire, Department of Virology, CHU, Caen, France;Laboratoire de Virologie, Department of Virology, Hôpital Saint-Vincent de Paul, Paris, France;Unité de Génétique, Papillomavirus et Cancer Humain, Department of Virology, Institut Pasteur, Paris, France

关键词: Phosphorylation;    STAT signaling;    Sendai virus;    Viral replication;    Plasmid construction;    Transfection;    Luciferase;    Signal inhibition;   

DOI  :  10.1371/journal.ppat.1000587

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY