Faculty Opinions recommendation of Investigation of the role of protein kinase D in human rhinovirus replication.
Year: 2017
Type: peer-review
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 concentrationdependent fashion and also blocked the replication of poliovirus (PV) and footand-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.IMPORTANCE Picornaviruses remain an important family of human and animal pathogens for which we have a very limited arsenal of antiviral agents.HRV is the causative agent of the common cold, which in itself is a relatively trivial infection; however, in asthma and chronic obstructive pulmonary disease (COPD) patients, this virus is a major cause of exacerbations resulting in an increased use of medication, worsening symptoms, and, frequently, hospital admission.Thus, HRV represents a substantial health care and economic burden for which there are no approved therapies.We sought to identify a novel host target as a potential anti-HRV therapy.HRV infection induces the phosphorylation of PKD, and inhibitors of this kinase effectively block HRV replication at an early stage of the viral life cycle.Moreover, PKD inhibitors also block PV and FMDV replication.This is the first description that PKD may represent a target for antiviral drug discovery.
Author: Johan Neyts
Institution: Rega Institute for Medical Research
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Awards: G1754370733, An effective vaccination programme for the eradication of foot-and-mouth disease from India, Modification of the host lipidome by Rhinovirus infection, Imperial Confidence in Concept: ICiC, G6144319358, Picornavirus capsid protein VP4: Essential role in cell entry and conserved antiviral target, G901458910
OpenAlex ID: W4254444536