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Author Notes:

To whom correspondence should be addressed: G.J. Nabel, e-mail: gnabel@nih.gov

Authors contributions and competing interests are listed on the first page of the article.

We thank M. A. Gawinowicz from the Protein Core Facility at Columbia University for MS analyses, Y. Shaul for c-Abl1 plasmids, B. Hartman and J. Farrar for figure preparation, A. Tislerics for manuscript editing, and members of the Nabel laboratory for discussions and advice. We also thank J. Nunneley from Texas Biomed for BSL4 technical assistance.

Subjects:

Research Funding:

This research was supported by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, U.S. NIH.

Live Ebola virus assays were conducted in Texas Biomed facilities constructed with support from the Research Facilities Improvement Program (grant number C06 RR012087) from the National Center for Research Resources.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Research & Experimental Medicine
  • MEDICINE, RESEARCH & EXPERIMENTAL
  • CHRONIC MYELOID-LEUKEMIA
  • ACTIN-BASED MOTILITY
  • MATRIX PROTEIN VP40
  • MARBURG VIRUS
  • VACCINIA VIRUS
  • BCR-ABL
  • NUCLEOPROTEIN
  • PARTICLES
  • IMATINIB

Productive Replication of Ebola Virus Is Regulated by the c-Abl1 Tyrosine Kinase

Tools:

Journal Title:

Science Translational Medicine

Volume:

Volume 4, Number 123

Publisher:

, Pages 123ra24-123ra24

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Ebola virus causes a fulminant infection in humans resulting in diffuse bleeding, vascular instability, hypotensive shock, and often death. Because of its high mortality and ease of transmission from human to human, Ebola virus remains a biological threat for which effective preventive and therapeutic interventions are needed. An understanding of the mechanisms of Ebola virus pathogenesis is critical for developing antiviral therapeutics. Here, we report that productive replication of Ebola virus is modulated by the c-Abl1 tyrosine kinase. Release of Ebola virus-like particles (VLPs) in a cell culture cotransfection system was inhibited by c-Abl1-specific small interfering RNA (siRNA) or by Abl-specific kinase inhibitors and required tyrosine phosphorylation of the Ebola matrix protein VP40. Expression of c-Abl1 stimulated an increase in phosphorylation of tyrosine 13 (Y 13) of VP40, and mutation of Y 13 to alanine decreased the release of Ebola VLPs. Productive replication of the highly pathogenic Ebola virus Zaire strain was inhibited by c-Abl1-specific siRNAs or by the Abl-family inhibitor nilotinib by up to four orders of magnitude. These data indicate that c-Abl1 regulates budding or release of filoviruses through a mechanism involving phosphorylation of VP40. This step of the virus life cycle therefore may represent a target for antiviral therapy.

Copyright information:

© 2012, American Association for the Advancement of Science

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