Porcine deltacoronavirus activates the Raf/MEK/ERK pathway to promote its replication

Abstract

Porcine deltacoronavirus (PDCoV) is a newly emerged swine coronavirus that causes acute enteritis in neonatal piglets. To date, little is known about the host factors or cellular signaling mechanisms associated with PDCoV replication. Since the Raf/MEK/ERK pathway is involved in modulation of various important cellular functions, numerous DNA and RNA viruses coopt this pathway for efficient propagation. In the present study, we found that PDCoV induces the activation of ERK1/2 and its downstream substrate Elk-1 early in infection irrespective of viral biosynthesis. Chemical inhibition or knockdown of ERK1/2 significantly suppressed viral replication, whereas treatment with an ERK activator increased viral yields. Direct pharmacological inhibition of ERK activation had no effect on the viral entry process but sequentially affected the post-entry steps of the virus life cycle. In addition, pharmacological sequestration of cellular or viral cholesterol downregulated PDCoV-induced ERK signaling, highlighting the significance of the cholesterol contents in ERK activation. However, ERK inhibition had no effect on PDCoV-triggered apoptosis through activation of the cytochrome c-mediated intrinsic mitochondrial pathway, suggesting the irrelevance of ERK activation to the apoptosis pathway during PDCoV infection. Altogether, our findings indicate that the ERK signaling pathway plays a pivotal role in viral biosynthesis to facilitate the optimal replication of PDCoV.

Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

“…Previous studies have revealed that inhibiting MAPK pathways can affect the expression of several viral proteins [ 28 , 35 , 36 ]. Thus, to explore a possible mechanism by which MAPK inhibitors affect MAYV replication, we used immunoblot to evaluate the structural E1 protein levels in cell lysates from MAYV-infected HDFs or HeLa cells treated with DMSO or the inhibitors SB203580, SP600125, or U0126 at different times post-infection.…”

Swine acute diarrhea syndrome coronavirus replication is reduced by inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway

“…These observations were similarly reproduced in the porcine intestinal epithelial cell line IPI-2I infected with infectious or UV-inactivated SADS-CoV, indicating that SADS-CoV-induced ERK signaling is independent of the cell type. Interestingly, other nidoviruses trigger similar ERK1/2 activation kinetics in response to viral entry, suggesting that the ERK pathway has a unique role in nidovirus biology ( Cai et al, 2007 ; Jeon et al, 2020 ; Kim and Lee, 2015 ; Lee and Lee, 2010 ). In other viruses, such as Human gammaherpesvirus 8, coxsackievirus B3, and human astrovirus, the rapid transient activation of the ERK pathway is observed within 10–15 min of infection ( Luo et al, 2002 ; Moser and Schultz-Cherry, 2008 ; Sharma-Walia et al, 2005 ).…”

“…Similarly, the following viruses also interact with ERK1/2: Hepatitis C virus ( Giambartolomei et al, 2001 ), Borna disease virus ( Planz et al, 2001 ), Influenza A virus ( Pleschka et al, 2001 ), and adenovirus type 7 ( Alcorn et al, 2001 ). For other coronaviruses such as Porcine deltacoronavirus (PDCoV)、Porcine epidemic diarrhea virus (PEDV)、Middle East respiratory syndrome coronavirus (MERS-CoV), it also has proved that ERK was specifically modulated in response to virus infection in vitro throughout the course of infection ( Jeon et al, 2020 ; Kim and Lee, 2015 ; Kindrachuk et al, 2015 ). Such widespread ERK involvement suggests either that it constitutes a global viral strategy to enhance the viral replicative machinery or that ERK1/2 activation is a universal response of the host to protect against infection.…”

“…Because viruses are obligate intracellular parasites, they have developed the ability to manipulate a variety of host-cell signal transduction pathways, including the ERK pathway, to benefit their own multiplication. Many viruses have been shown to exploit the ERK pathway for maximal viral replication and gene expression ( Jeon et al, 2020 ; Kim and Lee, 2015 ; Lee and Lee, 2010 ). However, the intracellular signaling mechanisms involved in SADS-CoV replication were unknown.…”

Anti-BRAF/Anti-MEK Targeted Therapies for Metastatic Melanoma Patients During the COVID-19 Outbreak: Experience from an Italian Skin Cancer Unit

“…Murine coronavirus mouse hepatitis virus induces the activation of the MAPK pathway, whereas the inhibition of the same pathway significantly impairs viral replication [ 14 ]. Data on porcine delta-coronavirus [ 15 ] and avian coronavirus infectious bronchitis virus [ 16 ] suggest that MEK/ERK signaling plays a major role in viral replication. Although these results were obtained with animal coronavirus and not with the new COVID-19 virus, hypotheses can be made of the potential important implications of the data in the frame of the ongoing COVID-19 pandemic.…”