The Epstein-Barr virus-induced Ca2+/calmodulin-dependent kinase type IV/Gr promotes a Ca(2+)-dependent switch from latency to viral replication.
The switch from latency to viral replication in Epstein-Barr virus (EBV)-transformed human B cells is mediated by Zta, the protein product of immediate-early EBV gene BZLF1. BZLF1 transcription is normally suppressed in EBV-transformed B cells but can be induced in some cell lines upon ligation of surface immunoglobulin by mechanisms that include the activation of Ca(2+)-dependent signaling pathways. The multifunctional Ca2+/calmodulin-dependent kinase type IV/Gr (CaMKIV/Gr) is normally absent in primary human B cells, but its expression is induced by the EBV oncoprotein LMP1 in the course of B-cell growth transformation by EBV. In this study, we demonstrate that activated CaMKIV/Gr induces transcription from the BZLF1 promoter and upregulates the expression of Zta in permissive cells. Transcriptional activation of the BZLF1 promoter by CaMKIV/Gr is dependent on the CREB/AP1 binding element ZII and is greatly augmented by the Ca2+/calmodulin-dependent phosphatase calcineurin. These results outline a virus-regulated mechanism involving CaMKIV/Gr which promotes transition from latency to productive viral replication in response to Ca(2+)-mobilizing extracellular signals.
Chatila
T
T
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Ho
N
N
Liu
P
P
Liu
S
S
Mosialos
G
G
Kieff
E
E
Speck
S H
SH
D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014764:Viral Proteins / Q000235:genetics* / Q000502:physiology; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication
C063676:BZLF1 protein, Herpesvirus 4, Human; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014764:Viral Proteins; C517683:CAMK4 protein, human; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium