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ADAP2 Is an Interferon Stimulated Gene That Restricts RNA Virus Entry

Shu, Q and Lennemann, NJ and Sarkar, SN and Sadovsky, Y and Coyne, CB (2015) ADAP2 Is an Interferon Stimulated Gene That Restricts RNA Virus Entry. PLoS Pathogens, 11 (9). ISSN 1553-7366

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Abstract

© 2015 Shu et al. Interferon stimulated genes (ISGs) target viruses at various stages of their infectious life cycles, including at the earliest stage of viral entry. Here we identify ArfGAP with dual pleckstrin homology (PH) domains 2 (ADAP2) as a gene upregulated by type I IFN treatment in a STAT1-dependent manner. ADAP2 functions as a GTPase-activating protein (GAP) for Arf6 and binds to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and PI(3,4)P2. We show that overexpression of ADAP2 suppresses dengue virus (DENV) and vesicular stomatitis virus (VSV) infection in an Arf6 GAP activity-dependent manner, while exerting no effect on coxsackievirus B (CVB) or Sendai virus (SeV) replication. We further show that ADAP2 expression induces macropinocytosis and that ADAP2 strongly associates with actin-enriched membrane ruffles and with Rab8a- and LAMP1-, but not EEA1- or Rab7-, positive vesicles. Utilizing two techniques—light-sensitive neutral red (NR)-containing DENV and fluorescence assays for virus internalization—we show that ADAP2 primarily restricts DENV infection at the stage of virion entry and/or intracellular trafficking and that incoming DENV and VSV particles associate with ADAP2 during their entry. Taken together, this study identifies ADAP2 as an ISG that exerts antiviral effects against RNA viruses by altering Arf6-mediated trafficking to disrupt viral entry.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Shu, Q
Lennemann, NJnil33@pitt.eduNIL33
Sarkar, SNsaumen@pitt.eduSAUMEN
Sadovsky, Yyos14@pitt.eduYOS14
Coyne, CB
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorGale Jr., MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, or Units > Magee-Women's Research Institute
Other Centers, Institutes, or Units > Pittsburgh Cancer Institute
Date: 1 January 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS Pathogens
Volume: 11
Number: 9
DOI or Unique Handle: 10.1371/journal.ppat.1005150
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Molecular Genetics
School of Medicine > Obstetrics, Gynecology, and Reproductive Sciences
Refereed: Yes
ISSN: 1553-7366
Date Deposited: 23 Aug 2016 13:38
Last Modified: 25 Jun 2018 13:57
URI: http://d-scholarship.pitt.edu/id/eprint/28572

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