Reprogramming the unfolded protein response for replication by porcine reproductive and respiratory syndrome virus
Year: 2019
Type: article
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. Author summaryPorcine reproductive and respiratory syndrome virus (PRRSV) poses a major threat to the worldwide swine industry, but no effective vaccines or antiviral drugs are available.A better understanding of the pathogen-host interactions that support PRRSV replication is essential for understanding viral pathogenesis and the development of preventive measures.Here we report that PRRSV utilizes unconventional strategies to reprogram the unfolded protein response (UPR) of the host to its own advantage.The virus targets GRP78 for partial degradation to create a favorable environment for UPR induction and hijacks ATF4 into cytoplasmic replication complexes to promote viral RNA synthesis.The data also reveal potential targets (e.g., ATF4 and XBP1s) for antiviral drugs and have implications in vaccine development.
Source: PLoS Pathogens
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,350
Funders: National Natural Science Foundation of China, Ministry of Science and Technology of the People's Republic of China, Ministry of Agriculture of the People's Republic of China, Penn State College of Medicine, Earmarked Fund for China Agriculture Research System, Thousand Young Talents Program of China
OpenAlex ID: W2988132987