-Adrenoreceptors Reactivate Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication via PKA-Dependent Control of Viral RTA

Department of Medicine, University of California, Los Angeles, Los Ángeles, California, United States
Journal of Virology (Impact Factor: 4.44). 12/2005; 79(21):13538-47. DOI: 10.1128/JVI.79.21.13538-13547.2005
Source: PubMed


Reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication is mediated by the viral RTA transcription
factor, but little is known about the physiological processes controlling its expression or activity. Links between autonomic
nervous system activity and AIDS-associated Kaposi's sarcoma led us to examine the potential influence of catecholamine neurotransmitters.
Physiological concentrations of epinephrine and norepinephrine efficiently reactivated lytic replication of KSHV in latently
infected primary effusion lymphoma cells via β-adrenergic activation of the cellular cyclic AMP/protein kinase A (PKA) signaling
pathway. Effects were blocked by PKA antagonists and mimicked by pharmacological and physiological PKA activators (prostaglandin
E2 and histamine) or overexpression of the PKA catalytic subunit. PKA up-regulated RTA gene expression, enhanced activity of the RTA promoter, and posttranslationally enhanced RTA's trans-activating capacity for its own promoter and heterologous lytic promoters (e.g., the viral PAN gene). Mutation of predicted phosphorylation targets at RTA serines 525 and 526 inhibited PKA-mediated enhancement of RTA
trans-activating capacity. Given the high catecholamine levels at sites of KSHV latency such as the vasculature and lymphoid organs,
these data suggest that β-adrenergic control of RTA might constitute a significant physiological regulator of KSHV lytic replication.
These findings also suggest novel therapeutic strategies for controlling the activity of this oncogenic gammaherpesvirus in

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    • "Central to this process is the fact that all major human tumor-associated viruses have been found to be responsive to beta-adrenergic receptor (ADRB) or glucocorticoid-dependent signaling cascades. For example, human herpesvirus 8, which induces Kaposi's sarcoma, possesses a cyclic adenosine monophosphate (cAMP) response element in the promoter of an important viral transcription factor (Chang et al., 2005). Additionally, ADRB stimulation of the viral host cell has been shown to increase cAMP response element binding (CREB)mediated expression of viral oncogenes and growth factors that Fig. 1. "
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    • "Increased intracellular Ca 2+ activated KSHV in a calcineurin/NFAT pathway in PEL and microvascular endothelial cells (MVEC) (Zoeteweij et al., 2001). The cAMP/PKA pathway activated by epinephrine/norepinephrine through β-adrenoreceptors (Chang et al., 2005), and dopamine derivatives by both PKA and MAPK pathways (Lee et al., 2008). Cellular modification of the latent nuclear antigen (LANA) (Cheng et al., 2009; Lu et al., 2006) and viral modification of cellular proteins (Sarek et al., 2010) are also indicated in controlling KSHV reactivation. "
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