Porcine parvovirus replication is suppressed by activation of the PERK signaling pathway and endoplasmic reticulum stress-mediated apoptosis

Abstract

Keywords:Porcine parvovirus Endoplasmic reticulum stress Unfolded protein response Protein kinase R-like ER kinase pathway Apoptotic cell death A B S T R A C T Endoplasmic reticulum (ER) stress is associated with numerous mammalian diseases, especially viral diseases. Porcine parvovirus (PPV) is the causative agent of reproductive failure in swine. Here, we observed that the PPV infection of porcine kidney 15 and porcine testis cells resulted in the activation of ER stress sensors mediated by protein kinase R-like ER kinase (PERK), but not inositol-requiring enzyme 1 and activating transcription factor 6 (ATF6). ER stress activation obviously blocked PPV replication. Depletion of proteins, such as PERK, eukaryotic initiation factor 2, and ATF4, by small interfering RNA significantly enhanced PPV replication. Moreover, the pro-apoptotic factor C/EBP homologous protein was identified a key factor in the inhibition of PPV replication. These data demonstrate that PPV infection activates ER stress through the PERK signaling pathway and that ER stress inhibits further PPV replication by promoting apoptosis.

Apoptin causes apoptosis inHepG‐2 cells via Ca2+imbalance and activation of the mitochondrial apoptotic pathway

“…The homeostatic balance created by the ER can, however, be disrupted by genetic and environmental damage, thus resulting in ER stress. In order to restore dynamic balance, the ER stress pathway is triggered and produces increased levels of several stress‐related proteins, including PERK, 22 , 23 , 24 IRE1 25 , 26 and ATF‐6. 27 , 28 , 29 Collectively, these proteins lighten the load on the ER by reducing misfolding and helping to avoid the accumulation of unfolded proteins.…”

Endoplasmic Reticulum Stress Mediated NLRP3 Inflammasome Activation and Pyroptosis in THP-1 Macrophages Infected with Bacillus Calmette-Guérin

“…In mild ERS, ER protects cells from damage by activating unfolded protein response (UPR) to remove misfolded proteins, and in excessive or persistent ERS, UPR stimulates autophagy, apoptosis and pyroptosis [8]. Downstream of UPR, there are three receptors: inositol-requiring enzyme 1 (IRE1), double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6) [9][10][11]. Studies have shown that Mtb can induce ERS in infected macrophages, thereby changing the fate of cells and Mtb [7,12].…”

Induction of the Unfolded Protein Response during Bovine Alphaherpesvirus 1 Infection

“…We then confirmed the impact of PERK on viral replication by using the PERK-specific inhibitor GSK2606414 to disrupt the PERK signaling pathway. Previous research revealed that ATF4 mRNA transcript levels could be elevated in response to the PERK pathway [ 59 , 60 , 61 ]. The PERK inhibition by GSK2606414 was detected by qPCR to analyze ATF4 mRNA levels ( Figure 4 E).…”