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Cell Microbiol. 2019 Jan;21(1):e12955. doi: 10.1111/cmi.12955. Epub 2018 Oct 23.

Late activation of the Raf/MEK/ERK pathway is required for translocation of the respiratory syncytial virus F protein to the plasma membrane and efficient viral replication.

Author information

1
Institute of Virology Muenster (IVM), Westfaelische Wilhelms-University (WWU) Muenster, Muenster, Germany.
2
The Graduate School of the Cluster of Excellence "Cells-in-Motion" (EXC 1003-CiM), WWU Muenster, Muenster, Germany.
3
Cluster of Excellence "Cells-in-Motion" (EXC 1003-CiM), WWU Muenster, Muenster, Germany.
4
Interdisciplinary Center of Clinical Research (IZKF), WWU Muenster, Muenster, Germany.
5
Section for Experimental Virology, Institute of Medical Microbiology, Jena University Hospital, Jena, Germany.

Abstract

Activation of the Raf/MEK/ERK cascade is required for efficient propagation of several RNA and DNA viruses, including human respiratory syncytial virus (RSV). In RSV infection, activation of the Raf/MEK/ERK cascade is biphasic. An early induction within minutes after infection is associated with viral attachment. Subsequently, a second activation occurs with, so far, unknown function in the viral life cycle. In this study, we aimed to characterise the role of Raf/MEK/ERK-mediated signalling during ongoing RSV infection. Our data show that inhibition of the kinase MEK after the virus has been internalised results in a reduction of viral titers. Further functional investigations revealed that the late-stage activation of ERK is required for a specific step in RSV replication, namely, the secretory transport of the RSV fusion protein F. Thus, MEK inhibition resulted in impaired surface accumulation of the F protein. F protein surface expression is essential for efficient replication as it is involved in viral filament formation, cell fusion, and viral transmission. In summary, we provide detailed insights of how host cell signalling interferes with RSV replication and identified the Raf/MEK/ERK kinase cascade as potential target for novel anti-RSV strategies.

PMID:
30223301
DOI:
10.1111/cmi.12955

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