Systematic identification of cellular signals reactivating Kaposi sarcoma-associated herpesvirus.
The herpesvirus life cycle has two distinct phases: latency and lytic replication. The balance between these two phases is critical for viral pathogenesis. It is believed that cellular signals regulate the switch from latency to lytic replication. To systematically evaluate the cellular signals regulating this reactivation process in Kaposi sarcoma-associated herpesvirus, the effects of 26,000 full-length cDNA expression constructs on viral reactivation were individually assessed in primary effusion lymphoma-derived cells that harbor the latent virus. A group of diverse cellular signaling proteins were identified and validated in their effect of inducing viral lytic gene expression from the latent viral genome. The results suggest that multiple cellular signaling pathways can reactivate the virus in a genetically homogeneous cell population. Further analysis revealed that the Raf/MEK/ERK/Ets-1 pathway mediates Ras-induced reactivation. The same pathway also mediates spontaneous reactivation, which sets the first example to our knowledge of a specific cellular pathway being studied in the spontaneous reactivation process. Our study provides a functional genomic approach to systematically identify the cellular signals regulating the herpesvirus life cycle, thus facilitating better understanding of a fundamental issue in virology and identifying novel therapeutic targets.
Yu
Fuqu
F
Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California, United States of America.
Harada
Josephine N
JN
Brown
Helen J
HJ
Deng
Hongyu
H
Song
Moon Jung
MJ
Wu
Ting-Ting
TT
Kato-Stankiewicz
Juran
J
Nelson
Christian G
CG
Vieira
Jeffrey
J
Tamanoi
Fuyuhiko
F
Chanda
Sumit K
SK
Sun
Ren
R
D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter / Q000502:physiology; D019288:Herpesvirus 8, Human / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D016483:Lymphoma, AIDS-Related / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014775:Virus Activation / Q000502:physiology*; D014779:Virus Replication / Q000235:genetics / Q000502:physiology; D048490:raf Kinases / Q000235:genetics / Q000502:physiology*
C494041:ETS1 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases