title: Productive replication of Ebola virus is regulated by the c-Abl1 tyrosine kinase.
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.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Mayra
authors.initials: M
authors.lastname: García
authors.forename: Arik
authors.initials: A
authors.lastname: Cooper
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: William
authors.initials: W
authors.lastname: Bornmann
authors.forename: Ricardo
authors.initials: R
authors.lastname: Carrion
authors.forename: Daniel
authors.initials: D
authors.lastname: Kalman
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002522:Chlorocebus aethiops; D003588:Cytopathogenic Effect, Viral; D029043:Ebolavirus / Q000145:classification / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D009698:Nucleoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine; D014709:Vero Cells; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057074:Virus Release; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D009698:Nucleoproteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014758:Viral Core Proteins; D014764:Viral Proteins; C084819:nucleoprotein VP40, Ebola virus; D014443:Tyrosine; D016315:Proto-Oncogene Proteins c-abl; C498826:nilotinib