PMID- 29321317 OWN - NLM STAT- MEDLINE DCOM- 20180417 LR - 20240326 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 92 IP - 7 DP - 2018 Apr 1 TI - The Wnt Signaling Pathway Is Differentially Expressed during the Bovine Herpesvirus 1 Latency-Reactivation Cycle: Evidence That Two Protein Kinases Associated with Neuronal Survival, Akt3 and BMPR2, Are Expressed at Higher Levels during Latency. LID - 10.1128/JVI.01937-17 [doi] LID - e01937-17 AB - Sensory neurons in trigeminal ganglia (TG) of calves latently infected with bovine herpesvirus 1 (BoHV-1) abundantly express latency-related (LR) gene products, including a protein (ORF2) and two micro-RNAs. Recent studies in mouse neuroblastoma cells (Neuro-2A) demonstrated ORF2 interacts with beta-catenin and a beta-catenin coactivator, high-mobility group AT-hook 1 (HMGA1) protein, which correlates with increased beta-catenin-dependent transcription and cell survival. beta-Catenin and HMGA1 are readily detected in a subset of latently infected TG neurons but not TG neurons from uninfected calves or reactivation from latency. Consequently, we hypothesized that the Wnt/beta-catenin signaling pathway is differentially expressed during the latency and reactivation cycle and an active Wnt pathway promotes latency. RNA-sequencing studies revealed that 102 genes associated with the Wnt/beta-catenin signaling pathway were differentially expressed in TG during the latency-reactivation cycle in calves. Wnt agonists were generally expressed at higher levels during latency, but these levels decreased during dexamethasone-induced reactivation. The Wnt agonist bone morphogenetic protein receptor 2 (BMPR2) was intriguing because it encodes a serine/threonine receptor kinase that promotes neuronal differentiation and inhibits cell death. Another differentially expressed gene encodes a protein kinase (Akt3), which is significant because Akt activity enhances cell survival and is linked to herpes simplex virus 1 latency and neuronal survival. Additional studies demonstrated ORF2 increased Akt3 steady-state protein levels and interacted with Akt3 in transfected Neuro-2A cells, which correlated with Akt3 activation. Conversely, expression of Wnt antagonists increased during reactivation from latency. Collectively, these studies suggest Wnt signaling cooperates with LR gene products, in particular ORF2, to promote latency.IMPORTANCE Lifelong BoHV-1 latency primarily occurs in sensory neurons. The synthetic corticosteroid dexamethasone consistently induces reactivation from latency in calves. RNA sequencing studies revealed 102 genes associated with the Wnt/beta-catenin signaling pathway are differentially regulated during the latency-reactivation cycle. Two protein kinases associated with the Wnt pathway, Akt3 and BMPR2, were expressed at higher levels during latency but were repressed during reactivation. Furthermore, five genes encoding soluble Wnt antagonists and beta-catenin-dependent transcription inhibitors were induced during reactivation from latency. These findings are important because Wnt, BMPR2, and Akt3 promote neurogenesis and cell survival, processes crucial for lifelong viral latency. In transfected neuroblastoma cells, a viral protein expressed during latency (ORF2) interacts with and enhances Akt3 protein kinase activity. These findings provide insight into how cellular factors associated with the Wnt signaling pathway cooperate with LR gene products to regulate the BoHV-1 latency-reactivation cycle. CI - Copyright (c) 2018 American Society for Microbiology. FAU - Workman, Aspen AU - Workman A AD - United States Department of Agriculture, Agricultural Research Service, U.S. Meat Animal Research Center, Clay Center, Nebraska, USA aspen.workman@ars.usda.gov clint.jones10@okstate.edu. FAU - Zhu, Liqian AU - Zhu L AD - Oklahoma State University Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA. AD - College of Veterinary Medicine and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, China. FAU - Keel, Brittney N AU - Keel BN AD - United States Department of Agriculture, Agricultural Research Service, U.S. Meat Animal Research Center, Clay Center, Nebraska, USA. FAU - Smith, Timothy P L AU - Smith TPL AD - United States Department of Agriculture, Agricultural Research Service, U.S. Meat Animal Research Center, Clay Center, Nebraska, USA. FAU - Jones, Clinton AU - Jones C AD - Oklahoma State University Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA aspen.workman@ars.usda.gov clint.jones10@okstate.edu. LA - eng GR - P20 GM103648/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20180314 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.30 (Bone Morphogenetic Protein Receptors, Type II) SB - IM MH - Animals MH - Bone Morphogenetic Protein Receptors, Type II/*biosynthesis/genetics MH - Cattle MH - Cell Survival MH - *Gene Expression Regulation, Enzymologic MH - Herpesvirus 1, Bovine/*physiology MH - Proto-Oncogene Proteins c-akt/*biosynthesis/genetics MH - Sensory Receptor Cells/*immunology/pathology/virology MH - Trigeminal Ganglion/*enzymology/pathology/virology MH - Virus Activation/*physiology MH - Virus Latency/*physiology MH - *Wnt Signaling Pathway PMC - PMC5972910 OTO - NOTNLM OT - Akt3 OT - ORF2 OT - Wnt signaling OT - bovine herpesvirus 1 OT - neuronal survival EDAT- 2018/01/13 06:00 MHDA- 2018/04/18 06:00 PMCR- 2018/09/14 CRDT- 2018/01/12 06:00 PHST- 2017/11/07 00:00 [received] PHST- 2018/01/04 00:00 [accepted] PHST- 2018/01/13 06:00 [pubmed] PHST- 2018/04/18 06:00 [medline] PHST- 2018/01/12 06:00 [entrez] PHST- 2018/09/14 00:00 [pmc-release] AID - JVI.01937-17 [pii] AID - 01937-17 [pii] AID - 10.1128/JVI.01937-17 [doi] PST - epublish SO - J Virol. 2018 Mar 14;92(7):e01937-17. doi: 10.1128/JVI.01937-17. Print 2018 Apr 1.