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ADAP2 Is an Interferon Stimulated Gene That Restricts RNA Virus Entry.

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Date
2015-09-15
Authors
Shu, Qian
Lennemann, Nicholas J
Sarkar, Saumendra N
Sadovsky, Yoel
Coyne, Carolyn B
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Abstract
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.
Type
Journal article
Subject
Cell Line
Vero Cells
Animals
Humans
Dengue Virus
Sendai virus
Vesiculovirus
Enterovirus B, Human
Virion
ADP-Ribosylation Factors
Phosphatidylinositol Phosphates
GTPase-Activating Proteins
Interferon-beta
Recombinant Fusion Proteins
Virus Replication
Pinocytosis
Mutation
STAT1 Transcription Factor
Virus Internalization
Chlorocebus aethiops
Permalink
https://hdl.handle.net/10161/22593
Published Version (Please cite this version)
10.1371/journal.ppat.1005150
Publication Info
Shu, Qian; Lennemann, Nicholas J; Sarkar, Saumendra N; Sadovsky, Yoel; & Coyne, Carolyn B (2015). ADAP2 Is an Interferon Stimulated Gene That Restricts RNA Virus Entry. PLoS pathogens, 11(9). pp. e1005150. 10.1371/journal.ppat.1005150. Retrieved from https://hdl.handle.net/10161/22593.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Carolyn Coyne

Professor of Molecular Genetics and Microbiology
We study the pathways by which microorganisms cross cellular barriers and the mechanisms by which these barriers restrict microbial infections. Our studies primarily focus on the epithelium that lines the gastrointestinal tract and on placental trophoblasts, the cells that comprise a key cellular barrier of the human placenta. Our work is highly multidisciplinary and encompasses aspects of cell biology, immunology, and microbiology. Our long-term goals are to identify pathogen- and host-spe
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