Control of the PI3K/Akt pathway by porcine reproductive and respiratory syndrome virus

Abstract

Phosphatidylinositol-3-kinase (PI3K)/Akt is an important cellular pathway that has been shown to participate in various replication steps of multiple viruses. In the present study, we compared the phosphorylation status of Akt during infection of MARC-145 cells and porcine alveolar macrophages (PAMs) with highly pathogenic PRRSV (HP-PRRSV) strain HuN4. We observed that biphasic activation of Akt was induced in at both the early stage (5, 15 and 30 min postinfection) and the late stage (12 and 24 h postinfection) of HP-PRRSV infection of MARC-145 cells, while an early-phase activation of Akt was found exclusively in virus-infected PAMs in vitro. Analysis with the PI3K-specific inhibitor LY294002 confirmed that PI3K acted as the upstream activator for the virus-induced activation of Akt. UV-irradiation-inactivated virus still induced the early event in PAMs but not in MARC-145 cells, suggesting that different mechanisms are employed for the early-stage induction of phosphorylated Akt within different cell cultures. We further demonstrated that FoxO1 and Bad, which serve as downstream targets of Akt, were phosphorylated in virus-infected MARC-145 cells. Moreover, the suppression of phosphorylated Akt with LY294002 significantly inhibited the virus-induced cytopathic effect (CPE) on MARC-145 cells, but it had a negligible effect on virus propagation. Collectively, our data provide new evidence of a novel role for the PI3K/Akt pathway in PRRSV infection of MARC-145 cells.

Autophagy postpones apoptotic cell death in PRRSV infection through Bad-Beclin1 interaction

“…PRRSV infection triggers Bad phosphorylation and results in regulating the interaction between Bad and Beclin1. Akt and ERK1/2 have been reported to function as physiologic Bad kinases and were required for PRRSV infection, 29,43,44 indicating that the interaction among Bad, Beclin1, Akt and ERK1/2 signaling pathway plays an important role for PRRSV infection.…”

Molecular and Cellular Mechanisms for PRRSV Pathogenesis and Host Response to Infection

“…The downstream target for PI3K is the AKT kinase that exerts the antiapoptotic effects by either phosphorylating some proapoptotic Bcl-2 family proteins or activating transcription factors to upregulate antiapoptotic genes. For PRRSV, the PI3K/Akt pathway is activated at an early stage of infection (Huo et al, 2013;Ni et al, 2015;Pujhari et al, 2014;Wang et al, 2016;Wang et al, 2014a;Zhang and Wang, 2010;Zhu et al, 2013). The Akt activation by PRRSV leads to negative regulation of the JNK pathway (Huo et al, 2013) and inhibits host cell apoptosis early in infection through inhibitory phosphorylation of pro-apoptotic protein Bad (Zhu et al, 2013).…”

Suppression of Virulent Porcine Epidemic Diarrhea Virus Proliferation by the PI3K/Akt/GSK-3α/β Pathway

“…Activated Akt induces the phosphorylation of numerous signaling proteins, including FoxO1, p53, mTOR, Bad, and glycogen synthase kinase-3 (GSK-3) [21][22][23][24][25]. The PI3K/Akt pathway affects the replication of many viruses, including human immunodeficiency virus (HIV), influenza virus, reovirus, herpesvirus, severe acute respiratory syndrome coronavirus (SARS-CoV), and the porcine reproductive and respiratory syndrome virus (PRRSV) [23,24,[26][27][28][29][30].…”