The CREB and AP-1–Dependent Cell Communication Network Factor 1 Regulates Porcine Epidemic Diarrhea Virus-Induced Cell Apoptosis Inhibiting Virus Replication Through the p53 Pathway

Abstract

Porcine epidemic diarrhea virus (PEDV) infection causes severe diarrhea, dehydration, and high mortality in sick pigs, causing huge economic losses to the pig industry. However, the relationship between cell communication network factor 1 (CCN1) and PEDV infection has not been reported. In this study, we showed that the expression of CCN1 was enhanced by PEDV infection, and we observed that PEDV promotes the CREB and AP-1 activation to promote CCN1 expression. The PKA and p38 inhibitors significantly suppress CCN1 expression, indicating that PEDV-induced CCN1 expression may be through PKA and p38 pathway. Further tests confirmed that CREB and AP-1 are regulated by PKA and p38, respectively. Overexpression of CCN1 decreased the replication of PEDV, whereas knockdown of CCN1 increased the replication of PEDV. We proved that the overexpression of CCN1 increased the phosphorylation level of p53, promoted the expresion of Bax and the cleavage of caspase 9 and caspase 3, and inhibited the production of Bcl-2. CCN1 knockdown decreased the phosphorylation level of p53, inhibited the production of Bax and the cleavage of caspase 9 and caspase 3, and promoted the expression of Bcl-2. The treatment of PFT-α (p53 inhibitor) significantly suppressed the expression of cleaved caspase 9 and caspase 3, leading to the decrease of apoptosis. Together, these studies showed that PEDV promotes the activation of CREB and AP-1 to increase the expression of CCN1. Overexpression of CCN1 promotes apoptosis by elevating p53 protein phosphorylation and inhibits PEDV replication, and knockdown of CCN1 inhibits apoptosis by decreasing p53 protein phosphorylation and promotes PEDV replication. Our study could provide some reference for the molecular mechanisms of PEDV-induced CCN1 induction and supply a new therapeutic target for PEDV.

The novel Nsp9-interacting host factor H2BE promotes PEDV replication by inhibiting endoplasmic reticulum stress-mediated apoptosis

“…In response to ER stress, high expression of CHOP promotes caspase activation through the upregulation of the proapoptotic protein Bax and downregulation of the antiapoptotic protein Bcl-2, leading to apoptosis. Our previous studies have shown that PEDV infection induces the initiation of intrinsic apoptosis pathways [ 12 , 32 ]. Our present study indicates that overexpression of H2BE promotes PEDV replication, downregulates CHOP expression in the PERK, eIF2, IRE1, and JNK pathways, decreases the expression of Bax, cleaved caspase-9 and cleaved caspase-3 and increases the expression of Bcl-2.…”

“…ZIKV inhibits apoptosis by suppressing the expression of CHOP/DDIT3 [ 11 ]. Our previous studies have shown that CCN1 inhibits viral replication by promoting PEDV-induced apoptosis via the mitochondrial pathway [ 12 ]. However, the mechanism by which apoptosis affects PEDV replication is not completely clear.…”

Differential expression analysis of mRNAs, lncRNAs, and miRNAs expression profiles and construction of ceRNA networks in PEDV infection

“…The kinetics of PEDV replication in Marc-145 cells showed that the viral RNA levels peaked at 48 hpi and decreased thereafter [ 41 ].Therefore, the samples from 24 and 48 hpi were selected for RNA sequencing. MARC-145 cells were divided into three groups: cells infected with PEDV for 24 h (S24hpi_1, 2, 3), cells infected with PEDV for 48 h (S48hpi_1, 2, 3), and mock-infected cells as controls (Mock_1, 2, 3).…”

Protumorigenic Interferon-Stimulated Genes in Cancer: A Comprehensive Review

“…These ISGs enhance the recruitment and activation of FADD. FADD is an adaptor molecule that transmits apoptotic signals from death receptors on the cell surface, such as the TRAIL receptors to initiate the caspase cascade [14][15][16].…”