CSFV induced mitochondrial fission and mitophagy to inhibit apoptosis.

Hongchao Gou,Wencheng He,Lin Yi,Jin Yuan,Hailuan Xu,Mengjiao Zhu,Hongxing Ding,Jinding Chen,Mingqiu Zhao

doi:10.18632/oncotarget.17030

Hongchao Gou, Wencheng He + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.17030

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Journal: Oncotarget	Publication Date: Apr 11, 2017
Citations: 53	License type: cc-by

Affiliation: South China Agricultural University

Abstract

Classical swine fever virus (CSFV), which causes typical clinical characteristics in piglets, including hemorrhagic syndrome and immunosuppression, is linked to hepatitis C and dengue virus. Oxidative stress and a reduced mitochondrial transmembrane potential are disturbed in CSFV-infected cells. The balance of mitochondrial dynamics is essential for cellular homeostasis. In this study, we offer the first evidence that CSFV induces mitochondrial fission and mitophagy to inhibit host cell apoptosis for persistent infection. The formation of mitophagosomes and decline in mitochondrial mass relevant to mitophagy were detected in CSFV-infected cells. CSFV infection increased the expression and mitochondrial translocation of Pink and Parkin. Upon activation of the PINK1 and Parkin pathways, Mitofusin 2 (MFN2), a mitochondrial fusion mediator, was ubiquitinated and degraded in CSFV-infected cells. Mitophagosomes and mitophagolysosomes induced by CSFV were, respectively, observed by the colocalization of LC3-associated mitochondria with Parkin or lysosomes. In addition, a sensitive dual fluorescence reporter (mito-mRFP-EGFP) was utilized to analyze the delivery of mitophagosomes to lysosomes. Mitochondrial fission caused by CSFV infection was further determined by mitochondrial fragmentation and Drp1 translocation into mitochondria using a confocal microscope. The preservation of mitochondrial proteins, upregulated apoptotic signals and decline of viral replication resulting from the silencing of Drp1 and Parkin in CSFV-infected cells suggested that CSFV induced mitochondrial fission and mitophagy to enhance cell survival and viral persistence. Our data for mitochondrial fission and selective mitophagy in CSFV-infected cells reveal a unique view of the pathogenesis of CSFV infection and provide new avenues for the development of antiviral strategies.

Highlights

Classical swine fever virus (CSFV), which is associated with hepatitis C and dengue virus, is an enveloped RNA virus that belongs to the Pestivirus within the family Flaviviridae [1, 2]
The preservation of mitochondrial proteins, upregulated apoptotic signals and decline of viral replication resulting from the silencing of dynaminrelated protein 1 (Drp1) and Parkin in CSFV-infected cells suggested that CSFV induced mitochondrial fission and mitophagy to enhance cell survival and viral persistence
We found that the expression and mitochondrial translocation of PINK1 and Parkin were increased by CSFV infection, and the degradation of Mitofusin2 (MFN2) via the ubiquitin pathway was upregulated in CSFV-infected cells

Summary

Introduction

Classical swine fever virus (CSFV), which is associated with hepatitis C and dengue virus, is an enveloped RNA virus that belongs to the Pestivirus within the family Flaviviridae [1, 2]. Different pathological changes are observed in pigs infected with strains of varied virulence. The complex interplay between CSFV and the host makes it difficult to eliminate [11]. Classical swine fever (CSF), the economically important animal disease worldwide, has been listed as A www.impactjournals.com/oncotarget by the OIE (World Organisation for Animal Health) [12]. No cytopathic effect is apparent when CSFV reproduces in host cells in vitro [13, 14]. Many studies related to the mechanism of CSFV replication have been performed, the pathogenesis of this virus is still poorly understood [15,16,17]

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