title: Quantitative Proteomic Analysis of Mosquito C6/36 Cells Reveals Host Proteins Involved in Zika Virus Infection.
abstract: Zika virus (ZIKV) is an emerging arbovirus belonging to the genusFlavivirusof the familyFlaviviridaeDuring replication processes, flavivirus manipulates host cell systems to facilitate its replication, while the host cells activate antiviral responses. Identification of host proteins involved in the flavivirus replication process may lead to the discovery of antiviral targets. The mosquitoesAedes aegyptiandAedes albopictusare epidemiologically important vectors for ZIKV, and effective restrictions of ZIKV replication in mosquitoes will be vital in controlling the spread of virus. In this study, an iTRAQ-based quantitative proteomic analysis of ZIKV-infectedAedes albopictusC6/36 cells was performed to investigate host proteins involved in the ZIKV infection process. A total of 3,544 host proteins were quantified, with 200 being differentially regulated, among which CHCHD2 can be upregulated by ZIKV infection in both mosquito C6/36 and human HeLa cells. Our further study indicated that CHCHD2 can promote ZIKV replication and inhibit beta interferon (IFN-β) production in HeLa cells, suggesting that ZIKV infection may upregulate CHCHD2 to inhibit IFN-I production and thus promote virus replication. Bioinformatics analysis of regulated host proteins highlighted several ZIKV infection-regulated biological processes. Further study indicated that the ubiquitin proteasome system (UPS) plays roles in the ZIKV entry process and that an FDA-approved inhibitor of the 20S proteasome, bortezomib, can inhibit ZIKV infectionin vivoOur study illustrated how host cells respond to ZIKV infection and also provided a candidate drug for the control of ZIKV infection in mosquitoes and treatment of ZIKV infection in patients.IMPORTANCEZIKV infection poses great threats to human health, and there is no FDA-approved drug available for the treatment of ZIKV infection. During replication, ZIKV manipulates host cell systems to facilitate its replication, while host cells activate antiviral responses. Identification of host proteins involved in the ZIKV replication process may lead to the discovery of antiviral targets. In this study, the first quantitative proteomic analysis of ZIKV-infected cells was performed to investigate host proteins involved in the ZIKV replication process. Bioinformatics analysis highlighted several ZIKV infection-regulated biological processes. Further study indicated that the ubiquitin proteasome system (UPS) plays roles in the ZIKV entry process and that an FDA-approved inhibitor of the UPS, bortezomib, can inhibit ZIKV infectionin vivoOur study not only illustrated how host cells respond to ZIKV infection but also provided a candidate drug for the control of ZIKV infection in mosquitoes and treatment of ZIKV infection in patients.
authors.affiliation: Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Qi-Lin
authors.initials: QL
authors.lastname: Xin
authors.affiliation: Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Cheng-Lin
authors.initials: CL
authors.lastname: Deng
authors.affiliation: Wuhan Institute of Biotechnology, Wuhan, China.|Medical Research Institute, Wuhan University, Wuhan, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Shao-Bo
authors.initials: SB
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Virology, Wuhan, China.|Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Virology, Wuhan, China.|Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Deng
authors.affiliation: Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Virology, Wuhan, China xiaogf@wh.iov.cn zhangleike@wh.iov.cn.|Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Gengfu
authors.initials: G
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Virology, Wuhan, China xiaogf@wh.iov.cn zhangleike@wh.iov.cn.|Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Lei-Ke
authors.initials: LK
authors.lastname: Zhang
mesh_terms: D000330:Aedes / Q000166:cytology / Q000187:drug effects / Q000502:physiology / Q000821:virology*; D000818:Animals; D000069286:Bortezomib / Q000008:administration & dosage / Q000627:therapeutic use; D002522:Chlorocebus aethiops; D019295:Computational Biology; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000037:antagonists & inhibitors; D051379:Mice; D000072138:Mosquito Vectors / Q000821:virology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D040901:Proteomics / Q000379:methods*; D014709:Vero Cells; D053586:Virus Internalization; D014779:Virus Replication / Q000187:drug effects; D000071244:Zika Virus / Q000502:physiology*; D000071243:Zika Virus Infection / Q000188:drug therapy / Q000821:virology
chemical_list: D019476:Insect Proteins; D000069286:Bortezomib; D016899:Interferon-beta; D046988:Proteasome Endopeptidase Complex
keywords: Zika virus; bortezomib; quantitative proteomics; ubiquitin proteasome system; virus-host interaction