PMID- 32796067 OWN - NLM STAT- MEDLINE DCOM- 20201230 LR - 20210414 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 94 IP - 21 DP - 2020 Oct 14 TI - Specific Akt Family Members Impair Stress-Mediated Transactivation of Viral Promoters and Enhance Neuronal Differentiation: Important Functions for Maintaining Latency. LID - 10.1128/JVI.00901-20 [doi] LID - e00901-20 AB - Neurotropic Alphaherpesvirinae subfamily members such as bovine herpesvirus 1 (BoHV-1) and herpes simplex virus 1 (HSV-1) establish and maintain lifelong latent infections in neurons. Following infection of ocular, oral, or nasal cavities, sensory neurons within trigeminal ganglia (TG) are an important site for latency. Certain external stressors can trigger reactivation from latency, in part because activation of the glucocorticoid receptor (GR) stimulates productive infection and promoters that drive expression of key viral transcriptional regulators. The Akt serine/threonine protein kinase family is linked to maintaining latency. For example, Akt3 is detected in more TG neurons during BoHV-1 latency than in reactivation and uninfected calves. Furthermore, Akt signaling correlates with maintaining HSV-1 latency in certain neuronal models of latency. Finally, an active Akt protein kinase is crucial for the ability of the HSV-1 latency-associated transcript (LAT) to inhibit apoptosis in neuronal cell lines. Consequently, we hypothesized that viral and/or cellular factors impair stress-induced transcription and reduce the incidence of reactivation triggered by low levels of stress. New studies demonstrate that Akt1 and Akt2, but not Akt3, significantly reduced GR-mediated transactivation of the BoHV-1 immediate early transcription unit 1 (IEtu1) promoter, the HSV-1 infected cell protein 0 (ICP0) promoter, and the mouse mammary tumor virus long terminal repeat (MMTV-LTR). Akt3, but not Akt1 or Akt2, significantly enhanced neurite formation in mouse neuroblastoma cells, which correlates with repairing damaged neurons. These studies suggest that unique biological properties of the three Akt family members promote the maintenance of latency in differentiated neurons.IMPORTANCE External stressful stimuli are known to increase the incidence of reactivation of Alphaherpesvirinae subfamily members. Activation of the glucocorticoid receptor (GR) by the synthetic corticosteroid dexamethasone (DEX) stimulates bovine herpesvirus 1 (BoHV-1) and herpes simplex virus 1 (HSV-1) reactivation. Furthermore, GR and dexamethasone stimulate productive infection and promoters that drive expression of viral transcriptional regulators. These observations lead us to predict that stress-induced transcription is impaired by factors abundantly expressed during latency. Interestingly, activation of the Akt family of serine/threonine protein kinases is linked to maintenance of latency. New studies reveal that Akt1 and Ak2, but not Akt3, impaired GR- and dexamethasone-mediated transactivation of the BoHV-1 immediate early transcription unit 1 and HSV-1 ICP0 promoters. Strikingly, Akt3, but not Akt1 or Akt2, stimulated neurite formation in mouse neuroblastoma cells, a requirement for neurogenesis. These studies provide insight into how Akt family members may promote the maintenance of lifelong latency. CI - Copyright (c) 2020 American Society for Microbiology. FAU - Zhao, Jing AU - Zhao J AD - Oklahoma State University, Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA. FAU - Zhu, Liqian AU - Zhu L AD - Oklahoma State University, Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA. FAU - Wijesekera, Nishani AU - Wijesekera N AD - Oklahoma State University, Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA. FAU - Jones, Clinton AU - Jones C AUID- ORCID: 0000-0002-6656-4971 AD - Oklahoma State University, Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA clint.jones10@okstate.edu. LA - eng GR - P20 GM103648/GM/NIGMS NIH HHS/United States GR - R01 NS111167/NS/NINDS 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 - 20201014 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Immediate-Early Proteins) RN - 0 (Receptors, Glucocorticoid) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.3.2.27 (Vmw110 protein, Human herpesvirus 1) RN - EC 2.7.11.1 (Akt1 protein, mouse) RN - EC 2.7.11.1 (Akt2 protein, mouse) RN - EC 2.7.11.1 (Akt3 protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Cattle MH - Cell Differentiation MH - Cell Line, Tumor MH - Herpes Simplex/genetics/*immunology/pathology/virology MH - Herpesviridae Infections/genetics/*immunology/pathology/virology MH - Herpesvirus 1, Bovine/genetics/immunology MH - Herpesvirus 1, Human/genetics/immunology MH - Host-Pathogen Interactions/genetics/*immunology MH - Humans MH - Immediate-Early Proteins/genetics/immunology MH - Mice MH - Neurites/immunology/ultrastructure/virology MH - Promoter Regions, Genetic MH - Proto-Oncogene Proteins c-akt/genetics/*immunology MH - Receptors, Glucocorticoid/genetics/immunology MH - Sensory Receptor Cells/immunology/pathology/*virology MH - Signal Transduction MH - Transcriptional Activation/immunology MH - Trigeminal Ganglion/immunology/pathology/virology MH - Ubiquitin-Protein Ligases/genetics/immunology PMC - PMC7565622 OTO - NOTNLM OT - AKT signaling OT - HSV-1 OT - bovine herpesvirus 1 OT - latency OT - neurogenesis OT - stress-induced transcription EDAT- 2020/08/17 06:00 MHDA- 2020/12/31 06:00 PMCR- 2021/04/14 CRDT- 2020/08/16 06:00 PHST- 2020/05/08 00:00 [received] PHST- 2020/07/30 00:00 [accepted] PHST- 2020/08/17 06:00 [pubmed] PHST- 2020/12/31 06:00 [medline] PHST- 2020/08/16 06:00 [entrez] PHST- 2021/04/14 00:00 [pmc-release] AID - JVI.00901-20 [pii] AID - 00901-20 [pii] AID - 10.1128/JVI.00901-20 [doi] PST - epublish SO - J Virol. 2020 Oct 14;94(21):e00901-20. doi: 10.1128/JVI.00901-20. Print 2020 Oct 14.