Reprogramming the unfolded protein response for replication by porcine reproductive and respiratory syndrome virus.

Abstract:

:The unfolded protein response (UPR) in the endoplasmic reticulum (ER) constitutes a critical component of host innate immunity against microbial infections. In this report, we show that porcine reproductive and respiratory syndrome virus (PRRSV) utilizes the UPR machinery for its own benefit. We provide evidence that the virus targets the UPR central regulator GRP78 for proteasomal degradation via a mechanism that requires viral glycoprotein GP2a, while both IRE1-XBP1s and PERK-eIF2α-ATF4 signaling branches of the UPR are turned on at early stage of infection. The activated effector XBP1s was found to enter the nucleus, but ATF4 was unexpectedly diverted to cytoplasmic viral replication complexes by means of nonstructural proteins nsp2/3 to promote viral RNA synthesis. RNAi knockdown of either ATF4 or XBP1s dramatically attenuated virus titers, while overexpression caused increases. These observations reveal attractive host targets (e.g., ATF4 and XBP1s) for antiviral drugs and have implications in vaccine development.

journal_name

PLoS Pathog

journal_title

PLoS pathogens

authors

Gao P,Chai Y,Song J,Liu T,Chen P,Zhou L,Ge X,Guo X,Han J,Yang H

doi

10.1371/journal.ppat.1008169

subject

Has Abstract

pub_date

2019-11-18 00:00:00

pages

e1008169

issue

11

eissn

1553-7366

issn

1553-7374

pii

PPATHOGENS-D-19-00844

journal_volume

15

pub_type

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