title: beta-Adrenoreceptors reactivate Kaposi's sarcoma-associated herpesvirus lytic replication via PKA-dependent control of viral RTA.
abstract: 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.
authors.affiliation: Department of Microbiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1678,USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Chang
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Brown
authors.forename: Alicia
authors.initials: A
authors.lastname: Collado-Hidalgo
authors.forename: Jesusa M
authors.initials: JM
authors.lastname: Arevalo
authors.forename: Zoran
authors.initials: Z
authors.lastname: Galic
authors.forename: Tonia L
authors.initials: TL
authors.lastname: Symensma
authors.forename: Lena
authors.initials: L
authors.lastname: Tanaka
authors.forename: Hongyu
authors.initials: H
authors.lastname: Deng
authors.forename: Jerome A
authors.initials: JA
authors.lastname: Zack
authors.forename: Ren
authors.initials: R
authors.lastname: Sun
authors.forename: Steve W
authors.initials: SW
authors.lastname: Cole
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004837:Epinephrine / Q000494:pharmacology; D019288:Herpesvirus 8, Human / Q000502:physiology*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014775:Virus Activation / Q000187:drug effects
chemical_list: D017874:Immediate-Early Proteins; D011943:Receptors, Adrenergic, beta; C417604:Rta protein, Human herpesvirus 8; D015534:Trans-Activators; D014764:Viral Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D009638:Norepinephrine; D004837:Epinephrine