Abstract
Herpesvirus replication involves the expression of over 80 viral genes in a well ordered sequence, leading to the production of new virions. Viral genes expressed during the earliest phases of replication often regulate both viral and cellular genes. Therefore, they have the potential to bring about dramatic functional changes within the cell. Replication and transcription activator (RTA) is a potent immediate early transcription activator of the gamma-herpesvirus family. This family includes Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus, human pathogens associated with malignancy. Here we combine gene array technology with transcription factor profiling to identify the earliest DNA promoter and cellular transcription factor targets of RTA in the cellular genome. We find that expression of RTA leads to both activation and inhibition of distinct groups of cellular genes. The identity of the target genes suggests that RTA rapidly changes the cellular environment to counteract cell death pathways, support growth factor signaling, and also promote immune evasion of the infected cell. Transcription factor profiling of the target gene promoters highlighted distinct pathways involved in gene activation at specific time points. Most notable throughout was the high level of cAMP-response element-binding protein (CREB)-response elements in RTA target genes. We find that RTA can function as either an activator or an inhibitor of CREB-response genes, depending on the promoter context. The association with CREB also highlights a novel connection and coordination between viral and cellular "immediate early" responses.
Highlights
The cellular environment plays a significant role in the outcome of virus infection, illustrated most clearly in the case of herpesvirus infections
How these processes are controlled by the cellular environment is of great interest, in the case of human ␥-herpesviruses (i.e. Epstein-Barr virus, Kaposi sarcoma-associated herpesvirus (KSHV3/HHV-8)) where infection has been linked to the development of malignancies, including lymphoma, nasopharyngeal carcinoma, gastric carcinoma, and Kaposi sarcoma [1– 6]
replication and transcription activator (RTA) is capable of activating transcription independently via direct promoter binding (19 –22), it can cooperate with a number of cellular transcription factors, such as Oct-1 [23, 24], the CCAAT/enhancer-binding protein (C/EBP) family [25], Notch coactivator RBP-J [26], and STAT3 [27]
Summary
The cellular environment plays a significant role in the outcome of virus infection, illustrated most clearly in the case of herpesvirus infections. Activation of the protein kinase A (PKA), RAS/MEK/ERK, and protein kinase C pathways [7–10] or inhibition of NF-B and Akt [11, 12] has been shown to reactivate the latent virus and restore lytic replication These cellular pathways are thought to regulate the balance between latency and lytic replication via expression of an immediate early viral gene product, replication and transcription activator (RTA). The sequence lies within a region required for binding of RTA to essential components of the cellular transcription machinery, including Brg and TRAP230, in addition to co-activator cyclic AMP-response element-binding protein (CREB)-binding protein (CBP) [13, 17, 18] Deletion of this region severely compromises the transcription activation and virus reactivation functions of RTA [13]. The number of different interacting partners and associated mechanisms of transcription regulation illustrates how RTA has adapted to utilize diverse cellular pathways to support virus replication
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