Cyclophilin A associates with enterovirus-71 virus capsid and plays an essential role in viral infection as an uncoating regulator

Jie Qing; Yaxin Wang; Yuna Sun; Jiaoyan Huang; Wenzhong Yan; Jinglan Wang; Dan Su; Cheng Ni; Jian Li; Zihe Rao; Lei Liu; Zhiyong Lou

doi:10.1371/journal.ppat.1004422

Cyclophilin A associates with enterovirus-71 virus capsid and plays an essential role in viral infection as an uncoating regulator

PLoS Pathog. 2014 Oct 2;10(10):e1004422. doi: 10.1371/journal.ppat.1004422. eCollection 2014 Oct.

Authors

Jie Qing¹, Yaxin Wang², Yuna Sun³, Jiaoyan Huang⁴, Wenzhong Yan⁵, Jinglan Wang⁴, Dan Su⁶, Cheng Ni⁷, Jian Li⁵, Zihe Rao², Lei Liu⁸, Zhiyong Lou⁹

Affiliations

¹ Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, China; School of Medicine, Tsinghua University, Beijing, China.
² School of Medicine, Tsinghua University, Beijing, China; National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, China.
³ National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, China.
⁴ School of Medicine, Tsinghua University, Beijing, China.
⁵ School of Pharmacy, East China University of Science and Technology, Shanghai, China.
⁶ Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
⁷ Beijing No. 4 High School, Beijing, China.
⁸ Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, China.
⁹ School of Medicine, Tsinghua University, Beijing, China; Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.

Abstract

Viruses utilize host factors for their efficient proliferation. By evaluating the inhibitory effects of compounds in our library, we identified inhibitors of cyclophilin A (CypA), a known immunosuppressor with peptidyl-prolyl cis-trans isomerase activity, can significantly attenuate EV71 proliferation. We demonstrated that CypA played an essential role in EV71 entry and that the RNA interference-mediated reduction of endogenous CypA expression led to decreased EV71 multiplication. We further revealed that CypA directly interacted with and modified the conformation of H-I loop of the VP1 protein in EV71 capsid, and thus regulated the uncoating process of EV71 entry step in a pH-dependent manner. Our results aid in the understanding of how host factors influence EV71 life cycle and provide new potential targets for developing antiviral agents against EV71 infection.

Publication types

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

MeSH terms

Antiviral Agents / pharmacology
Capsid / metabolism*
Capsid Proteins / metabolism*
Cyclophilin A / metabolism*
Enterovirus A, Human / drug effects
Enterovirus A, Human / genetics*
Enterovirus A, Human / metabolism*
Humans
Virus Replication / drug effects

Substances

Antiviral Agents
Capsid Proteins
Cyclophilin A

Grants and funding

This work was supported by the Ministry of Science and Technology 973 (grant no. 2013CB911103 and 2014CB542800), the National Natural Science Foundation of China (grant nos. 81322023, 91313301, 31170678, 31370733 and 31000332), and The Importation and Development of High-Caliber Talents Project of Beijing Municipal Institutions (grant no. YETP0166). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.