PMID- 26739046 OWN - NLM STAT- MEDLINE DCOM- 20160722 LR - 20181113 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 90 IP - 6 DP - 2016 Jan 6 TI - beta-Catenin, a Transcription Factor Activated by Canonical Wnt Signaling, Is Expressed in Sensory Neurons of Calves Latently Infected with Bovine Herpesvirus 1. PG - 3148-59 LID - 10.1128/JVI.02971-15 [doi] AB - Like many Alphaherpesvirinae subfamily members, bovine herpesvirus 1 (BoHV-1) expresses an abundant transcript in latently infected sensory neurons, the latency-related (LR)-RNA. LR-RNA encodes a protein (ORF2) that inhibits apoptosis, interacts with Notch family members, interferes with Notch-mediated transcription, and stimulates neurite formation in cells expressing Notch. An LR mutant virus containing stop codons at the amino terminus of ORF2 does not reactivate from latency or replicate efficiently in certain tissues, indicating that LR gene products are important. In this study, beta-catenin, a transcription factor activated by the canonical Wnt signaling pathway, was frequently detected in ORF2-positive trigeminal ganglionic neurons of latently infected, but not mock-infected, calves. Conversely, the lytic cycle regulatory protein (BoHV-1 infected cell protein 0, or bICP0) was not frequently detected in beta-catenin-positive neurons in latently infected calves. During dexamethasone-induced reactivation from latency, mRNA expression levels of two Wnt antagonists, Dickkopf-1 (DKK-1) and secreted Frizzled-related protein 2 (SFRP2), were induced in bovine trigeminal ganglia (TG), which correlated with reduced beta-catenin protein expression in TG neurons 6 h after dexamethasone treatment. ORF2 and a coactivator of beta-catenin, mastermind-like protein 1 (MAML1), stabilized beta-catenin protein levels and stimulated beta-catenin-dependent transcription in mouse neuroblastoma cells more effectively than MAML1 or ORF2 alone. Neuroblastoma cells expressing ORF2, MAML1, and beta-catenin were highly resistant to cell death following serum withdrawal, whereas most cells transfected with only one of these genes died. The Wnt signaling pathway interferes with neurodegeneration but promotes neuronal differentiation, suggesting that stabilization of beta-catenin expression by ORF2 promotes neuronal survival and differentiation. IMPORTANCE: Bovine herpesvirus 1 (BoHV-1) is an important pathogen of cattle, and like many Alphaherpesvirinae subfamily members establishes latency in sensory neurons. Lifelong latency and the ability to reactivate from latency are crucial for virus transmission. Maintaining the survival and normal functions of terminally differentiated neurons is also crucial for lifelong latency. Our studies revealed that BoHV-1 gene products expressed during latency stabilize expression of the transcription factor beta-catenin and perhaps its cofactor, mastermind-like protein 1 (MAML1). In contrast to expression during latency, beta-catenin expression in sensory neurons is not detectable following treatment of latently infected calves with the synthetic corticosteroid dexamethasone to initiate reactivation from latency. A viral protein (ORF2) expressed in a subset of latently infected neurons stabilized beta-catenin and MAML1 in transfected cells. ORF2, beta-catenin, and MAML1 also enhanced cell survival when growth factors were withdrawn, suggesting that these genes enhance survival of latently infected neurons. CI - Copyright (c) 2016, American Society for Microbiology. All Rights Reserved. FAU - Liu, Yilin AU - Liu Y AD - School of Veterinary Medicine and Biomedical Sciences, Nebraska Center for Virology, Morrison Life Sciences Research Center, University of Nebraska-Lincoln, Lincoln, Nebraska, USA. FAU - Hancock, Morgan AU - Hancock M AD - School of Veterinary Medicine and Biomedical Sciences, Nebraska Center for Virology, Morrison Life Sciences Research Center, University of Nebraska-Lincoln, Lincoln, Nebraska, USA. FAU - Workman, Aspen AU - Workman A AD - U.S. Department of Agriculture, Agricultural Research Service, U.S. Meat Animal Research Center, Clay Center, Nebraska, USA. FAU - Doster, Alan AU - Doster A AD - School of Veterinary Medicine and Biomedical Sciences, Nebraska Center for Virology, Morrison Life Sciences Research Center, University of Nebraska-Lincoln, Lincoln, Nebraska, USA. FAU - Jones, Clinton AU - Jones C AD - School of Veterinary Medicine and Biomedical Sciences, Nebraska Center for Virology, Morrison Life Sciences Research Center, University of Nebraska-Lincoln, Lincoln, Nebraska, USA clint.jones10@okstate.edu. LA - eng GR - P20 RR015635/RR/NCRR NIH HHS/United States GR - 1P20RR15635/RR/NCRR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20160106 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Viral Proteins) RN - 0 (beta Catenin) SB - IM MH - Animals MH - Cattle MH - Cattle Diseases/virology MH - Herpesviridae Infections/veterinary/virology MH - Herpesvirus 1, Bovine/*physiology MH - *Host-Pathogen Interactions MH - Sensory Receptor Cells/*virology MH - Trigeminal Ganglion/virology MH - Viral Proteins/*metabolism MH - *Virus Latency MH - *Wnt Signaling Pathway MH - beta Catenin/*biosynthesis PMC - PMC4810647 EDAT- 2016/01/08 06:00 MHDA- 2016/07/23 06:00 PMCR- 2016/08/26 CRDT- 2016/01/08 06:00 PHST- 2015/11/23 00:00 [received] PHST- 2015/12/30 00:00 [accepted] PHST- 2016/01/08 06:00 [entrez] PHST- 2016/01/08 06:00 [pubmed] PHST- 2016/07/23 06:00 [medline] PHST- 2016/08/26 00:00 [pmc-release] AID - JVI.02971-15 [pii] AID - 02971-15 [pii] AID - 10.1128/JVI.02971-15 [doi] PST - epublish SO - J Virol. 2016 Jan 6;90(6):3148-59. doi: 10.1128/JVI.02971-15.