Investigation of the Role of Protein Kinase D in Human Rhinovirus Replication

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Title: Investigation of the Role of Protein Kinase D in Human Rhinovirus Replication
Authors: Guedan, A
Swieboda, D
Charles, M
Toussaint, M
Johnston, SL
Asfor, A
Panjwani, A
Tuthill, TJ
Danahay, H
Raynham, T
Mousnier, A
Solari, R
Item Type: Journal Article
Abstract: Picornavirus replication is known to cause extensive remodeling of Golgi and endoplasmic reticulum membranes, and a number of the host proteins involved in the viral replication complex have been identified, including oxysterol binding protein (OSBP) and phosphatidylinositol 4-kinase III beta (PI4KB). Since both OSBP and PI4KB are substrates for protein kinase D (PKD) and PKD is known to be involved in the control of Golgi membrane vesicular and lipid transport, we hypothesized that PKD played a role in viral replication. We present multiple lines of evidence in support of this hypothesis. First, infection of HeLa cells with human rhinovirus (HRV) induced the phosphorylation of PKD. Second, PKD inhibitors reduced HRV genome replication, protein expression, and titers in a concentration-dependent fashion and also blocked the replication of poliovirus (PV) and foot-and-mouth disease virus (FMDV) in a variety of cells. Third, HRV replication was significantly reduced in HeLa cells overexpressing wild-type and mutant forms of PKD1. Fourth, HRV genome replication was reduced in HAP1 cells in which the PKD1 gene was knocked out by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9. Although we have not identified the molecular mechanism through which PKD regulates viral replication, our data suggest that this is not due to enhanced interferon signaling or an inhibition of clathrin-mediated endocytosis, and PKD inhibitors do not need to be present during viral uptake. Our data show for the first time that targeting PKD with small molecules can inhibit the replication of HRV, PV, and FMDV, and therefore, PKD may represent a novel antiviral target for drug discovery.
Issue Date: 22-Feb-2017
Date of Acceptance: 10-Feb-2017
URI: http://hdl.handle.net/10044/1/48294
DOI: https://dx.doi.org/10.1128/JVI.00217-17
ISSN: 0022-538X
Publisher: American Society for Microbiology
Journal / Book Title: Journal of Virology
Volume: 91
Issue: 9
Copyright Statement: © 2017 Guedán et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: National Institute for Health Research
Medical Research Council (MRC)
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: Project No. 7021
R1608-M0398
ICiC funding 2015/16
Keywords: Science & Technology
Life Sciences & Biomedicine
Virology
Golgi membrane
protein kinase D
antiviral
picornavirus
rhinovirus
viral replication
OXYSTEROL-BINDING PROTEIN
MOUTH-DISEASE VIRUS
D-MEDIATED PHOSPHORYLATION
ENTEROVIRUS REPLICATION
PICORNAVIRUS REPLICATION
SECRETORY PATHWAY
GOLGI-APPARATUS
III-BETA
IN-VIVO
C-MU
Golgi membrane
antiviral
picornavirus
protein kinase D
rhinovirus
viral replication
Animals
Cell Line, Tumor
Cricetinae
DNA Replication
DNA, Viral
Foot-and-Mouth Disease Virus
Gene Knockout Techniques
HeLa Cells
Humans
Interferon Type I
Phosphorylation
Poliovirus
Protein Kinase C
Pyrimidines
Rhinovirus
Virus Replication
Virology
06 Biological Sciences
07 Agricultural And Veterinary Sciences
11 Medical And Health Sciences
Publication Status: Published
Article Number: e00217-17
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine



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