Raf/MEK/ERK signalling triggers reactivation of Kaposi's sarcoma-associated herpesvirus latency.
Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. KSHV infection of cells produces both latent and lytic cycles of infection. In vivo, the virus is found predominantly in the latent state. In vitro, a lytic infection can be induced in KSHV-infected cells by treating with phorbol ester (TPA). However, the exact signalling events that lead to the reactivation of KSHV lytic infection are still elusive. Here, a role is demonstrated for B-Raf/MEK/ERK signalling in TPA-induced reactivation of KSHV latent infection. Inhibiting MEK/ERK signalling by using MEK-specific inhibitors decreased expression of the TPA-induced KSHV lytic-cycle gene ORF8. Transfection of BCBL-1 cells with B-Raf small interfering RNA inhibited TPA-induced KSHV lytic infection significantly. Additionally, overexpression of MEK1 induced a lytic cycle of KSHV infection in BCBL-1 cells. The significance of these findings in understanding the biology of KSHV-associated pathogenesis is discussed.
Ford
Patrick W
PW
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA.
Bryan
Benjaman A
BA
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA.
Dyson
Ossie F
OF
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA.
Weidner
Douglas A
DA
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA.
Chintalgattu
Vishnu
V
Department of Physiology, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA.
Akula
Shaw M
SM
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA.
D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D015398:Signal Transduction; D014775:Virus Activation
D010703:Phorbol Esters; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases