Productive replication of ebola virus is regulated by the c-Abl1 tyrosine kinase

Mayra García, Arik Cooper, Wei Shi, William Bornmann, Ricardo Carrion, Daniel Kalman, Gary J. Nabel

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number123ra24
JournalScience Translational Medicine
Volume4
Issue number123
DOIs
StatePublished - Feb 29 2012
Externally publishedYes

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Ebolavirus
Protein-Tyrosine Kinases
Phosphorylation
Virion
Antiviral Agents
Tyrosine
Life Cycle Stages
Alanine
Small Interfering RNA
Blood Vessels
Shock
Phosphotransferases
Therapeutics
Cell Culture Techniques
Hemorrhage
Viruses
Mutation
Mortality
Infection

ASJC Scopus subject areas

  • Medicine(all)

Cite this

García, M., Cooper, A., Shi, W., Bornmann, W., Carrion, R., Kalman, D., & Nabel, G. J. (2012). Productive replication of ebola virus is regulated by the c-Abl1 tyrosine kinase. Science Translational Medicine, 4(123), [123ra24]. https://doi.org/10.1126/scitranslmed.3003500

Productive replication of ebola virus is regulated by the c-Abl1 tyrosine kinase. / García, Mayra; Cooper, Arik; Shi, Wei; Bornmann, William; Carrion, Ricardo; Kalman, Daniel; Nabel, Gary J.

In: Science Translational Medicine, Vol. 4, No. 123, 123ra24, 29.02.2012.

Research output: Contribution to journalArticle

García, M, Cooper, A, Shi, W, Bornmann, W, Carrion, R, Kalman, D & Nabel, GJ 2012, 'Productive replication of ebola virus is regulated by the c-Abl1 tyrosine kinase', Science Translational Medicine, vol. 4, no. 123, 123ra24. https://doi.org/10.1126/scitranslmed.3003500
García, Mayra ; Cooper, Arik ; Shi, Wei ; Bornmann, William ; Carrion, Ricardo ; Kalman, Daniel ; Nabel, Gary J. / Productive replication of ebola virus is regulated by the c-Abl1 tyrosine kinase. In: Science Translational Medicine. 2012 ; Vol. 4, No. 123.
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