CSFV Infection Up-Regulates the Unfolded Protein Response to Promote Its Replication.

Wencheng He,Jinding Chen,Mingqiu Zhao,Shaofeng Deng,Yuming Chen,Yangyi Zhang,Jin Yuan,Hongchao Gou,Hailuan Xu,Jiedan Liao,Shuangqi Fan,Baoming Xie

doi:10.3389/fmicb.2017.02129

Wencheng He, Jinding Chen + Show 10 more

Open Access

https://doi.org/10.3389/fmicb.2017.02129

Copy DOI

Abstract

Classical swine fever (CSF) is an OIE-listed, highly contagious animal disease caused by classical swine fever virus (CSFV). The endoplasmic reticulum (ER) is an organelle in which the replication of many RNA viruses takes place. During viral infection, a series of events elicited in cells can destroy the ER homeostasis that cause ER stress and induce an unfolded protein response (UPR). In this study, we demonstrate that ER stress was induced during CSFV infection as several UPR-responsive elements such as XBP1(s), GRP78 and CHOP were up-regulated. Specifically, CSFV transiently activated IRE1 pathway at the initial stage of infection but rapidly switched off, likely due to the reduction in cytoplasm Ca2+ after viral incubation. Additionally, our data show that the ER stress induced by CSFV can promote CSFV production, which the IRE1 pathway play an important role in it. Evidence of ER stress in vivo was also confirmed by the marked elevation of GRP78 in CSFV-infected pig PBMC and tissues. Collectively, these data indicate that the ER stress was induced upon CSFV infection and that the activation of the IRE1 pathway benefits CSFV replication.

Highlights

The endoplasmic reticulum (ER) is a extensive cellular membranous structure that provides a special environment for lipid biosynthesis, protein folding and secretion, and calcium homeostasis (Healy et al, 2012)
classical swine fever virus (CSFV) Transiently Activates the IRE1 Pathway during or Soon after Virion Entry To determine whether the unfolded protein response (UPR) is activated upon CSFV infection, PK-15 was infected with CSFV at an multiplicity of infection (MOI) of 1
GRP78, the major indicator of ER stress can be induced by X-Box binding Protein-1 (XBP1)(s) or ATF6, was up-regulated early at 3 h.p.i., with a peak at 6 h.p.i. and a gradual reduction to basal levels at later stages of infection (24 h.p.i, Figure 1B), strongly suggesting that the IRE1-XBP1 signal is responsible for the up-regulation of GRP78

Summary

Introduction

The ER is a extensive cellular membranous structure that provides a special environment for lipid biosynthesis, protein folding and secretion, and calcium homeostasis (Healy et al, 2012). The UPR is comprised of three branches: IRE1 (inositol-requiring enzyme 1), PERK (PKRlike ER protein kinase), and ATF6 (activating transcription factor 6). Under normal conditions, these three sensor proteins are sequestered by 78 KD glucose-regulated protein (GRP78), an ER chaperone that acts as a master regulator of the UPR and the up-regulation of which reflects the activation of the UPR program. The spliced form of XBP1 [XBP1(s)] encodes a protein acts as CSFV Infection Induce ER Stress a potent transcriptional activator of many genes including chaperones, phospholipid biosynthesis enzymes and the ER degradation-enhancing alpha-mannosidase-like protein (EDEM), which is involved in the ER-associated protein degradation (ERAD) pathway. Under serious ER stress, UPR can induce apoptosis for the benefit of the entire organisms (Zhang and Kaufman, 2004; Malhotra and Kaufman, 2007; Bravo et al, 2013)

Methods

Results

Conclusion