Format

Send to

Choose Destination
Cell Rep. 2019 May 28;27(9):2579-2592.e6. doi: 10.1016/j.celrep.2019.04.105.

Reciprocal Effects of Fibroblast Growth Factor Receptor Signaling on Dengue Virus Replication and Virion Production.

Author information

1
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 344, Heidelberg 69120, Germany.
2
Biomedical Computer Vision Group, Heidelberg University, BioQuant, IPMB, and German Cancer Research Center, Im Neuenheimer Feld 267, Heidelberg 69120, Germany.
3
ViroQuant Research Group Modeling, BioQuant, Heidelberg University, Heidelberg, Germany.
4
Advanced Biological Screening Facility, BioQuant, Heidelberg University, Heidelberg 69120, Germany.
5
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 344, Heidelberg 69120, Germany; Institut National de la Recherche Scientifique, Institut Armand-Frappier, 531, Boulevard des Prairies Laval, Québec, QC H7V 1B7, Canada.
6
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 344, Heidelberg 69120, Germany; German Center for Infection Research, Heidelberg Partner Site, Im Neuenheimer Feld 344, Heidelberg 69120, Germany. Electronic address: ralf.bartenschlager@med.uni-heidelberg.de.

Abstract

Dengue virus (DENV) is a human arboviral pathogen accounting for 390 million infections every year. The available vaccine has limited efficacy, and DENV-specific drugs have not been generated. To better understand DENV-host cell interaction, we employed RNA interference-based screening of the human kinome and identified fibroblast growth factor receptor 4 (FGFR4) to control the DENV replication cycle. Pharmacological inhibition of FGFR exerts a reciprocal effect by reducing DENV RNA replication and promoting the production of infectious virus particles. Addressing the latter effect, we found that the FGFR signaling pathway modulates intracellular distribution of DENV particles in a PI3K-dependent manner. Upon FGFR inhibition, virions accumulate in the trans-Golgi network compartment, where they undergo enhanced maturation cleavage of the envelope protein precursor membrane (prM), rendering virus particles more infectious. This study reveals an unexpected reciprocal role of a cellular receptor tyrosine kinase regulating DENV RNA replication and the production of infectious virions.

KEYWORDS:

DENV; FGFR-4; RNAi-based screen; dependency factors; flaviviruses; furin; host-pathogen interactions; human kinome; proteolytic cleavage; restriction factors

PMID:
31141684
DOI:
10.1016/j.celrep.2019.04.105
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center