title: Regulation of Notch-mediated transcription by a bovine herpesvirus 1 encoded protein (ORF2) that is expressed in latently infected sensory neurons.
abstract: Bovine herpesvirus 1 (BoHV-1) is an Alphaherpesvirinae subfamily member that establishes life-long latency in sensory neurons. The latency-related RNA (LR-RNA) is abundantly expressed during latency. An LR mutant virus containing stop codons at the amino-terminus of open reading frame (ORF)2 does not reactivate from latency and replicates less efficiently in tonsils and trigeminal ganglia. ORF2 inhibits apoptosis, interacts with Notch family members, and interferes with Notch-dependent transcription suggesting ORF2 expression enhances survival of infected neurons. The Notch signaling pathway is crucial for neuronal differentiation and survival suggesting that interactions between ORF2 and Notch family members regulate certain aspects of latency. Consequently, for this study, we compared whether ORF2 interfered with the four mammalian Notch family members. ORF2 consistently interfered with Notch1-3-mediated transactivation of three cellular promoters. Conversely, Notch4-mediated transcription was not consistently inhibited by ORF2. Electrophoretic shift mobility assays using four copies of a consensus-DNA binding site for Notch/CSL (core binding factor (CBF)-1, Suppressor of Hairless, Lag-2) as a probe revealed ORF2 interfered with Notch1 and 3 interactions with a CSL family member bound to DNA. Additional studies demonstrated ORF2 enhances neurite sprouting in mouse neuroblastoma cells that express Notch1-3, but not Notch4. Collectively, these studies indicate that ORF2 inhibits Notch-mediated transcription and signaling by interfering with Notch interacting with CSL bound to DNA.
authors: School of Veterinary Medicine and Biomedical Sciences, Nebraska Center for Virology, Morisson Life Science Center, University of Nebraska, Lincoln, Lincoln, NE, 68583-0900, USA.
authors: Yilin
authors: Y
authors: Liu
authors: School of Veterinary Medicine and Biomedical Sciences, Nebraska Center for Virology, Morisson Life Science Center, University of Nebraska, Lincoln, Lincoln, NE, 68583-0900, USA. clint.jones@okstate.edu.|Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Oklahoma State University, 157C McElroy Hall, Stillwater, OK, 74078, USA. clint.jones@okstate.edu.
authors: Clinton
authors: C
authors: Jones
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D050660:Core Binding Factors / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D007242:Herpesvirus 1, Bovine; D054884:Host-Pathogen Interactions; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000821:virology*; D016366:Open Reading Frames; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism; D000071656:Receptor, Notch3 / Q000235:genetics / Q000378:metabolism; D000074562:Receptor, Notch4 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014775:Virus Activation; D017735:Virus Latency
chemical_list: D050660:Core Binding Factors; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D014764:Viral Proteins; D004247:DNA
keywords: BoHV-1; Latency in sensory neurons; Neuronal differentiation; Notch-mediated transcription; ORF2