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

English version

Autoři: Peng Gao ^aff001; Yue Chai ^aff001; Jiangwei Song ^aff001; Teng Liu ^aff001; Peng Chen ^aff001; Lei Zhou ^aff001; Xinna Ge ^aff001; Xin Guo ^aff001; Jun Han ^aff001; Hanchun Yang ^aff001
Působiště autorů: Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, China Agricultural University College of Veterinary Medicine, Beijing, People’s Republic of China ^aff001
Vyšlo v časopise: Reprogramming the unfolded protein response for replication by porcine reproductive and respiratory syndrome virus. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1008169
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008169

Souhrn

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.

Klíčová slova:

Antibodies – Confocal microscopy – Messenger RNA – RNA synthesis – RNA viruses – Small interfering RNAs – Transfection – Viral replication

Zdroje

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