Enteroviral 2B Interacts with VDAC3 to Regulate Reactive Oxygen Species Generation That Is Essential to Viral Replication

Mei-Ling Cheng; Chien-Hsiang Wu; Kun-Yi Chien; Chien-Hsueh Lai; Guan-Jie Li; Yuan-Yu Liu; Gigin Lin; Hung-Yao Ho

doi:10.3390/v14081717

Enteroviral 2B Interacts with VDAC3 to Regulate Reactive Oxygen Species Generation That Is Essential to Viral Replication

Viruses. 2022 Aug 4;14(8):1717. doi: 10.3390/v14081717.

Authors

Mei-Ling Cheng^{1

2

3

4

5}, Chien-Hsiang Wu⁶, Kun-Yi Chien⁷, Chien-Hsueh Lai⁶, Guan-Jie Li⁵, Yuan-Yu Liu⁶, Gigin Lin^{4

8

9

10}, Hung-Yao Ho^{2

3

4

5

6

11}

Affiliations

¹ Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan.
² Healthy Aging Research Center, Chang Gung University, Taoyuan City 33302, Taiwan.
³ Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan City 33302, Taiwan.
⁴ Clinical Metabolomics Core Laboratory, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33302, Taiwan.
⁵ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan.
⁶ Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan.
⁷ Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan.
⁸ Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33302, Taiwan.
⁹ Imaging Core Laboratory, Institute for Radiological Research, Chang Gung University, Taoyuan City 33302, Taiwan.
¹⁰ Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan City 33302, Taiwan.
¹¹ Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan City 33302, Taiwan.

Abstract

Enterovirus (EV) 71 caused episodes of outbreaks in China and Southeast Asia during the last few decades. We have previously reported that EV71 induces reactive oxygen species (ROS). However, the underlying mechanism remains elusive. Co-immunoprecipitation-proteomic analysis revealed that enteroviral 2B protein interacted with mitochondrial voltage-dependent anion channel 3 (VDAC3). Knockdown (KD) of VDAC3 expression specifically inhibited enteroviral replication. Single-round viral replication was also inhibited in KD cells, suggesting that VDAC3 plays an essential role in replication. Consistent with this, VDAC3 gene KD significantly reduced the EV71-induced mitochondrial ROS generation. Exogenous 2B expression could induce the mitochondrial ROS generation that was significantly reduced in VDAC3-KD cells or in the Mito-TEMPO-treated cells. Moreover, VDAC3 appears to be necessary for regulation of antioxidant metabolism. VDAC3 gene KD led to the enhancement of such pathways as hypotaurine/taurine synthesis in the infected cells. Taken together, these findings suggest that 2B and VDAC3 interact to enhance mitochondrial ROS generation, which promotes viral replication.

Keywords: EV71; VDAC3; reactive oxygen species.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Enterovirus A, Human* / metabolism
Mitochondria / metabolism
Picornaviridae* / metabolism
Proteomics
Reactive Oxygen Species / metabolism
Virus Replication
Voltage-Dependent Anion Channels / genetics
Voltage-Dependent Anion Channels / metabolism

Substances

Reactive Oxygen Species
Voltage-Dependent Anion Channels

Grants and funding

This research was funded by Chang Gung Memorial Hospital (grant number: BMRP819, BMRP564, CMRPD1J0342, CMRPD1L0161, CMRPD1L0162, CMRPD1M0351, CMRPD1J0263 and CMRPD1M0341), Ministry of Science and Technology in Taiwan (MOST) (grant number: 110-2320-B-182-017-MY3, 110-2320-B-182-007 and 111-2320-B-182-011), and Ministry of Education in Taiwan (MOE) (EMRPD1K0441, EMRPD1K0481, and EMRPD1L0421). This work was also supported by the Research Center for Emerging Viral Infections from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan and the Ministry of Science and Technology (MOST), Taiwan (MOST 111-2634-F-182-001).