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Porcine epidemic diarrhea virus induces caspase-independent apoptosis through activation of mitochondrial apoptosis-inducing factor.

ABSTRACT: The present study sought to investigate whether porcine epidemic diarrhea virus (PEDV) induces apoptosis and to elucidate the mechanisms associated with apoptotic cell death after PEDV infection. PEDV-infected cells showed evidence of apoptosis in vitro and in vivo. However, experimental data indicated that the caspase cascade is not involved in PEDV-induced apoptotic cell death. Interestingly, mitochondrial apoptosis-inducing factor (AIF) was found to translocate to the nucleus during PEDV infection, and AIF relocalization was completely abrogated by the presence of cyclosporin A (CsA), an inhibitor of cyclophilin D (CypD) that is an essential component of the mitochondrial permeabilization transition pore (mPTP) complex. CsA treatment resulted in significant inhibition of PEDV-triggered apoptosis and suppressed PEDV replication. Furthermore, direct inhibition of AIF strongly impaired PEDV infection and virus-induced apoptosis. Altogether, our results indicate that a caspase-independent mitochondrial AIF-mediated pathway plays a central role in PEDV-induced apoptosis to facilitate viral replication and pathogenesis.

SUBMITTER: Kim Y

PROVIDER: S-EPMC7127720 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Porcine epidemic diarrhea virus induces caspase-independent apoptosis through activation of mitochondrial apoptosis-inducing factor.

Kim Youngnam Y Lee Changhee C

Virology 20140605

The present study sought to investigate whether porcine epidemic diarrhea virus (PEDV) induces apoptosis and to elucidate the mechanisms associated with apoptotic cell death after PEDV infection. PEDV-infected cells showed evidence of apoptosis in vitro and in vivo. However, experimental data indicated that the caspase cascade is not involved in PEDV-induced apoptotic cell death. Interestingly, mitochondrial apoptosis-inducing factor (AIF) was found to translocate to the nucleus during PEDV infe ...[more]

PMID: 25010284

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Project description:Berberine, an isoquinoline alkaloid derived from plants, is a traditional medicine for treating bacterial diarrhea and intestinal parasite infections. Although berberine has recently been shown to suppress growth of several tumor cell lines, information regarding the effect of berberine on colon tumor growth is limited. Here, we investigated the mechanisms underlying the effects of berberine on regulating the fate of colon tumor cells, specifically the mouse immorto-Min colonic epithelial (IMCE) cells carrying the Apc(min) mutation, and of normal colon epithelial cells, namely young adult mouse colonic epithelium (YAMC) cells. Berberine decreased colon tumor colony formation in agar, and induced cell death and LDH release in a time- and concentration-dependent manner in IMCE cells. In contrast, YAMC cells were not sensitive to berberine-induced cell death. Berberine did not stimulate caspase activation, and PARP cleavage and berberine-induced cell death were not affected by a caspase inhibitor in IMCE cells. Rather, berberine stimulated a caspase-independent cell death mediator, apoptosis-inducing factor (AIF) release from mitochondria and nuclear translocation in a ROS production-dependent manner. Amelioration of berberine-stimulated ROS production or suppression of AIF expression blocked berberine-induced cell death and LDH release in IMCE cells. Furthermore, two targets of ROS production in cells, cathepsin B release from lysosomes and PARP activation were induced by berberine. Blockage of either of these pathways decreased berberine-induced AIF activation and cell death in IMCE cells. Thus, berberine-stimulated ROS production leads to cathepsin B release and PARP activation-dependent AIF activation, resulting in caspase-independent cell death in colon tumor cells. Notably, normal colon epithelial cells are less susceptible to berberine-induced cell death, which suggests the specific inhibitory effects of berberine on colon tumor cell growth.

Dataset Information

Porcine epidemic diarrhea virus induces caspase-independent apoptosis through activation of mitochondrial apoptosis-inducing factor.

Publications

Porcine epidemic diarrhea virus induces caspase-independent apoptosis through activation of mitochondrial apoptosis-inducing factor.

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