PMID- 31776270 OWN - NLM STAT- MEDLINE DCOM- 20200821 LR - 20211204 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 94 IP - 4 DP - 2020 Jan 31 TI - Two Pioneer Transcription Factors, Kruppel-Like Transcription Factor 4 and Glucocorticoid Receptor, Cooperatively Transactivate the Bovine Herpesvirus 1 ICP0 Early Promoter and Stimulate Productive Infection. LID - 10.1128/JVI.01670-19 [doi] LID - e01670-19 AB - An important site for bovine herpesvirus 1 (BoHV-1) latency is sensory neurons within trigeminal ganglia (TG). The synthetic corticosteroid dexamethasone consistently induces BoHV-1 reactivation from latency. Expression of four Kruppel-like transcription factors (KLF), i.e., KLF4, KLF6, PLZF (promyelocytic leukemia zinc finger), and KLF15, are induced in TG neurons early during dexamethasone-induced reactivation. The glucocorticoid receptor (GR) and KLF15 form a feed-forward transcription loop that cooperatively transactivates the BoHV-1 immediate early transcription unit 1 (IEtu1) promoter that drives bovine infected cell protein 0 (bICP0) and bICP4 expression. Since the bICP0 gene also contains a separate early (E) promoter, we tested the hypothesis that GR and KLF family members transactivate the bICP0 E promoter. GR and KLF4, both pioneer transcription factors, cooperated to stimulate bICP0 E promoter activity in a ligand-independent manner in mouse neuroblastoma cells (Neuro-2A). Furthermore, GR and KLF4 stimulated productive infection. Mutating both half GR binding sites did not significantly reduce GR- and KLF4-mediated transactivation of the bICP0 E promoter, suggesting that a novel mechanism exists for transactivation. GR and KLF15 cooperatively stimulated bICP0 activity less efficiently than GR and KL4: however, KLF6, PLZF, and GR had little effect on the bICP0 E promoter. GR, KLF4, and KLF15 occupied bICP0 E promoter sequences in transfected Neuro-2A cells. GR and KLF15, but not KLF4, occupied the bICP0 E promoter at late times during productive infection of bovine cells. Collectively, these studies suggest that cooperative transactivation of the bICP0 E promoter by two pioneer transcription factors (GR and KLF4) correlates with stimulating lytic cycle viral gene expression following stressful stimuli.IMPORTANCE Bovine herpesvirus 1 (BoHV-1), an important bovine pathogen, establishes lifelong latency in sensory neurons. Reactivation from latency is consistently induced by the synthetic corticosteroid dexamethasone. We predict that increased corticosteroid levels activate the glucocorticoid receptor (GR). Consequently, viral gene expression is stimulated by the activated GR. The immediate early transcription unit 1 promoter (IEtu1) drives expression of two viral transcriptional regulatory proteins, bovine infected cell protein 0 (bICP0) and bICP4. Interestingly, a separate early promoter also drives bICP0 expression. Two pioneer transcription factors, GR and Kruppel-like transcription factor 4 (KLF4), cooperatively transactivate the bICP0 early (E) promoter. GR and KLF15 cooperate to stimulate bICP0 E promoter activity but significantly less than GR and KLF4. The bICP0 E promoter contains enhancer-like domains necessary for GR- and KLF4-mediated transactivation that are distinct from those for GR and KLF15. Stress-induced pioneer transcription factors are proposed to activate key viral promoters, including the bICP0 E promoter, during early stages of reactivation from latency. CI - Copyright (c) 2020 American Society for Microbiology. FAU - El-Mayet, Fouad S AU - El-Mayet FS AD - Oklahoma State University, Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA. FAU - Sawant, Laximan AU - Sawant L AD - Oklahoma State University, Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA. FAU - Thunuguntla, Prasanth AU - Thunuguntla P AD - Oklahoma State University, Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA. FAU - Zhao, Jing AU - Zhao J AD - Oklahoma State University, Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA. FAU - Jones, Clinton AU - Jones C 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 - R21 NS102290/NS/NINDS 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 - 20200131 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Immediate-Early Proteins) RN - 0 (Klf15 protein, mouse) RN - 0 (Klf4 protein, mouse) RN - 0 (Kruppel-Like Factor 4) RN - 0 (Kruppel-Like Transcription Factors) RN - 0 (Receptors, Glucocorticoid) RN - 0 (Trans-Activators) RN - 0 (Transcription Factor 4) RN - 0 (Transcription Factors) RN - 0 (Viral Proteins) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.3.2.27 (bICP0 protein, Bovine herpesvirus 1) SB - IM MH - Animals MH - Binding Sites MH - Cattle MH - Cell Line MH - Gene Expression Regulation, Viral/genetics MH - Herpesviridae Infections/metabolism/virology MH - Herpesvirus 1, Bovine/metabolism/pathogenicity MH - Immediate-Early Proteins/metabolism MH - Kruppel-Like Factor 4 MH - Kruppel-Like Transcription Factors/*metabolism/physiology MH - Mice MH - Promoter Regions, Genetic/genetics MH - Receptors, Glucocorticoid/*metabolism MH - Trans-Activators/*metabolism MH - Transcription Factor 4/metabolism MH - Transcription Factors/metabolism MH - Trigeminal Ganglion/virology MH - Ubiquitin-Protein Ligases/*metabolism MH - Viral Proteins/metabolism MH - Virus Activation/genetics PMC - PMC6997752 OTO - NOTNLM OT - bovine herpesvirus 1 OT - gene expression OT - pioneer transcription factor OT - stress response EDAT- 2019/11/30 06:00 MHDA- 2020/08/22 06:00 PMCR- 2020/07/31 CRDT- 2019/11/29 06:00 PHST- 2019/09/27 00:00 [received] PHST- 2019/11/14 00:00 [accepted] PHST- 2019/11/30 06:00 [pubmed] PHST- 2020/08/22 06:00 [medline] PHST- 2019/11/29 06:00 [entrez] PHST- 2020/07/31 00:00 [pmc-release] AID - JVI.01670-19 [pii] AID - 01670-19 [pii] AID - 10.1128/JVI.01670-19 [doi] PST - epublish SO - J Virol. 2020 Jan 31;94(4):e01670-19. doi: 10.1128/JVI.01670-19. Print 2020 Jan 31.