beta-Adrenoreceptors reactivate Kaposi's sarcoma-associated herpesvirus lytic replication via PKA-dependent control of viral RTA.

Titlebeta-Adrenoreceptors reactivate Kaposi's sarcoma-associated herpesvirus lytic replication via PKA-dependent control of viral RTA.
Publication TypeJournal Article
Year of Publication2005
AuthorsChang M, Brown HJ, Collado-Hidalgo A, Arevalo JM, Galic Z, Symensma TL, Tanaka L, Deng H, Zack JA, Sun R, Cole SW
JournalJ Virol
Date Published2005 Nov
KeywordsAnimals, Cell Line, Cells, Cultured, Cyclic AMP-Dependent Protein Kinases, Epinephrine, Herpesvirus 8, Human, Immediate-Early Proteins, Norepinephrine, Promoter Regions, Genetic, Receptors, Adrenergic, beta, Signal Transduction, Trans-Activators, Viral Proteins, Virus Activation

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 beta-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 beta-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 vivo.

Alternate JournalJ. Virol.
PubMed ID16227274
PubMed Central IDPMC1262578
Grant ListAI 36554 / AI / NIAID NIH HHS / United States
AI36059 / AI / NIAID NIH HHS / United States
AI49135 / AI / NIAID NIH HHS / United States
AI52737 / AI / NIAID NIH HHS / United States
CA91971 / CA / NCI NIH HHS / United States
DE14153 / DE / NIDCR NIH HHS / United States