Differential regulation of type I interferon and epidermal growth factor pathways by a human Respirovirus virulence factor.
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.
Caignard
Grégory
G
Laboratoire de Génomique Virale et Vaccination, Department of Virology, Institut Pasteur, CNRS URA 3015, Paris, France.
Komarova
Anastassia V
AV
Bouraï
Mehdi
M
Mourez
Thomas
T
Jacob
Yves
Y
Jones
Louis M
LM
Rozenberg
Flore
F
Vabret
Astrid
A
Freymuth
François
F
Tangy
Frédéric
F
Vidalain
Pierre-Olivier
PO
D000818:Animals; D001665:Binding Sites; D002452:Cell Count; D002460:Cell Line; D002522:Chlorocebus aethiops; D004815:Epidermal Growth Factor / Q000378:metabolism*; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005434:Flow Cytometry; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D007370:Interferon Type I / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010224:Parainfluenza Virus 3, Human / Q000378:metabolism* / Q000472:pathogenicity; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D015203:Reproducibility of Results; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014709:Vero Cells; D014764:Viral Proteins / Q000378:metabolism; D037521:Virulence Factors / Q000378:metabolism*
D039561:Eukaryotic Initiation Factor-4E; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D007370:Interferon Type I; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014764:Viral Proteins; D037521:Virulence Factors; D004815:Epidermal Growth Factor; D016899:Interferon-beta; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases