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Regulation of Notch-mediated transcription by a bovine herpesvirus 1 encoded protein (ORF2) that is expressed in latently infected sensory neurons

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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.

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References

  • Allen SJ, Rhode-Kurnow A, Mott KR, Jiang X, Carpenter D, Rodriguez-Barbosa JI, Jones C, Wechsler SL, Ware CF, Ghiasi H (2014) Interactions between herpesvirus entry mediator (TNFRSF14) and latency-associated transcript during herpes simplex virus 1 latency. J Virol 88:1961–1971

    Article  PubMed  PubMed Central  Google Scholar 

  • Berezovska O, McLean P, Knowles R, Frosh M, Lu FM, Lux SE, Hyman BT (1999) Notch1 inhibits neurite outgrowth in postmitotic primary neurons. Neuroscience 93:433–439

    Article  CAS  PubMed  Google Scholar 

  • Borggrefe T, Oswald E (2009) The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci 66:1631–1646

    Article  CAS  PubMed  Google Scholar 

  • Brakenhoff RH (2011) Another Notch for cancer. Science 333:1102–1103

    Article  CAS  PubMed  Google Scholar 

  • Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7:678–689

    Article  CAS  PubMed  Google Scholar 

  • Ciacci-Zanella J, Stone M, Henderson G, Jones C (1999) The latency-related gene of bovine herpesvirus 1 inhibits programmed cell death. J Virol 73:9734–9740

    CAS  PubMed  PubMed Central  Google Scholar 

  • Coleman MP, Freeman MR (2010) Wallerian degeneration (Wld(S) and nmnat. Annu Rev Neurosci 33:245–267

    Article  CAS  PubMed  Google Scholar 

  • Cornell R, Eisen JS (2005) Notch in the pathway: the roles of Notch signalling in neural crest development. Semin Cell Dev Biol 16:663–672

    Article  CAS  PubMed  Google Scholar 

  • Devireddy LR, Jones C (1998) Alternative splicing of the latency-related transcript of bovine herpesvirus 1 yields RNAs containing unique open reading frames. J Virol 72:7294–7301

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ehebauer M, Penelope P, Arias AM (2006) Notch, a universial arbiter of cell fate decisions. Science 314:1414–1415

    Article  CAS  PubMed  Google Scholar 

  • El Bejjani R, Hammerlund M (2012) Notch signaling inhibits axon regeneration. Neuron 73:268–278

    Article  PubMed  PubMed Central  Google Scholar 

  • Franklin JL, Berechid BE, Cutting FB, Presente A, Chambers CB, Folz DR, Ferreira A, Nye JS (1999) Autonomous and non-autonomous regulation of mammalian neurite development by Notch1 and Delta1. Curr Biol 9:1448–1457

    Article  CAS  PubMed  Google Scholar 

  • Fryer CJ, White JB, Jones KA (2004) Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol Cell 16:509–520

    Article  CAS  PubMed  Google Scholar 

  • Hardy KM, Krischmann DA, Seftor EA, Margaryan NV, Postovit LM, Strizzi L, Hendrix MJ (2010) Regulation of the embryonic morphogen nodal by Notch4 facilitates manifestation of the aggressive melanoma phenotype. Cancer Res 70:10340–10350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hitoshi S, Alexson T, Tropepe V, Donoviel D, Elia A, Nye J, Conlon R, Mak T, Bernstein A, van der Kooy D (2002) Notch pathway molecules are essential for the maintenace, but not the generation, of mammalian neural stem cells. Genes Dev 16:846–858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inman M, Lovato L, Doster A, Jones C (2001) A mutation in the latency-related gene of bovine herpesvirus 1 leads to impaired ocular shedding in acutely infected calves. J Virol 75:8507–8515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inman M, Lovato L, Doster A, Jones C (2002) A mutation in the latency-related gene of bovine herpesvirus 1 disrupts the latency reactivation cycle in calves. J Virol 76:6771–6779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jaber T, Workman A, Jones C (2010) Small noncoding RNAs encoded within the bovine herpesvirus 1 latency-related gene can reduce steady-state levels of infected cell protein 0 (bICP0). J Virol 84:6297–6307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • James AC, Szot JO, Iyer K, Major JA, Pursglove SE, Chapman G, Dunwoodie SL (2014) Notch4 reveals a novel mechanism regulating Notch signal transduction. Biochem Biophys Acta 1843:1272–1284

    Article  CAS  PubMed  Google Scholar 

  • Jones C (1998) Alphaherpesvirus latency: its role in disease and survival of the virus in nature. Adv Virus Res 51:81–133

    Article  CAS  PubMed  Google Scholar 

  • Jones C (2003) Herpes simplex virus type 1 and bovine herpesvirus 1 latency. Clin Microbiol Rev 16:79–95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones C (2009) Regulation of innate immune responses by bovine herpesvirus 1 and infected cell protein 0. Virus 1:255–275

    Article  CAS  Google Scholar 

  • Jones C (2015) Reactivation from latency by α-herpesvirinae submfamily members: a stressful stimulation. Trends Virol

  • Jones C, Chowdhury S (2007) A review of the biology of bovine herpesvirus type 1 (BHV-1), its role as a cofactor in the bovine respiratory disease complex, and development of improved vaccines. Adv Anim Health 8:187–205

    Article  Google Scholar 

  • Jones C, Geiser V, Henderson G, Jiang Y, Meyer F, Perez S, Zhang Y (2006) Functional analysis of bovine herpesvirus 1 (BHV-1) genes expressed during latency. Vet Microbiol 113:199–210

    Article  CAS  PubMed  Google Scholar 

  • Jones C, da Silva LF, Sinani D (2011) Regulation of the latency-reactivation cycle by products encoded by the bovine herpesvirus 1 (BHV-1) latency-related gene. J Neurovirol 17:535–545

    Article  CAS  PubMed  Google Scholar 

  • Justice NJ, Jan YN (2002) Variations on the Notch pathway in neural development. Curr Opin Neurobiol 12:64–70

    Article  CAS  PubMed  Google Scholar 

  • Kitamoto T, Hanaoka K (2010) Notch3 null mutation in mice causes muscle hyperplasia by repetitive muscle regeneration. Stem Cells 28:2205–2216

    Article  CAS  PubMed  Google Scholar 

  • Koch U, Radtke F (2011) Notch in T-ALL: new players in a complex disease. Trends Immunol 32:434–442

    Article  CAS  PubMed  Google Scholar 

  • Krebs LT, Xue Y, Norton CR, Sunberg JP, Beatus P, Lendahl U, Joutel A, Gridley T (2003) Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation. Genesis 37:139–143

    Article  CAS  PubMed  Google Scholar 

  • Kutish G, Mainprize T, Rock D (1990) Characterization of the latency-related transcriptionally active region of the bovine herpesvirus 1 genome. J Virol 64:5730–5737

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lassiter RN, Ball MK, Adams JS, Wright BT, Stark MR (2010) Sensory neuron differentiation is regulated by notch signaling in the trigeminal placode. Dev Biol 344:836–848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levy DE, Darnell JE Jr (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651–662

    Article  CAS  PubMed  Google Scholar 

  • Levy OA, Lah JJ, Levy AI (2002) Notch signaling inhibits PC12 cell neurite outgrowth via RBP-J-dependent and -independent mechanisms. Dev Neurosci 24:79–88

    Article  CAS  PubMed  Google Scholar 

  • Liu H, Chi AWS, Arnett KA, Chiang MY, Xu L, Shestova O, Wang H, Li Y-M, Bhandoola A, Aster JC, Blacklow SC, Pear WS (2010) Notch dimerization is required for leukemogenesis and T-cell development. Genes Dev 24:2396–2407

    Google Scholar 

  • Lovato L, Inman M, Henderson G, Doster A, Jones C (2003) Infection of cattle with a bovine herpesvirus 1 (BHV-1) strain that contains a mutation in the latency related gene leads to increased apoptosis in trigeminal ganglia during the transition from acute infection to latency. J Virol 77:4848–4857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meyer F, Jones C (2008) C/EBP-alpha cooperates with bTIF to activate the bovine herpesvirus 1 immediate early transcription unit 1 promoter. J Neurovirol 2:1–8

    Google Scholar 

  • Meyer F, Perez S, Jiang Y, Zhou Y, Henderson G, Jones C (2007) Identification of a novel protein encoded by the latency-related gene of bovine herpesvirus 1. J Neurovirol 13:569–578

    Article  CAS  PubMed  Google Scholar 

  • Mott K, Osorio N, Jin L, Brick D, Naito J, Cooper J, Henderson G, Inman M, Jones C, Wechsler SL, Perng G-C (2003) The bovine herpesvirus 1 LR ORF2 is crucial for this gene’s ability to restore the high reactivation phenotype to a herpes simplex virus-1 LAT null mutant. J Gen Virol 84:2975–2985

    Article  CAS  PubMed  Google Scholar 

  • Nagamatsu I, Onishi H, Matsushita S, Kubo M, Kai M, Imaizumi A, Nakano K, Hattori M, Oda Y, Tanaka M, Katano M (2014) Notch4 is a potential therpaeutic target for triple-negative breast cancer. Anticancer Res 34:69–80

    CAS  PubMed  Google Scholar 

  • Naidr P, Somasundaram K, Krishna S (2003) Activated Notch1 inhibits p53-induced apoptosis and sustains transformation by human papilloma virus type 16 E6 and E7 oncogenes through a PI3K-PKB/Akt-dependent pathway. J Virol 77:7106–7112

    Article  Google Scholar 

  • Ohtsuka T, Ishibashi M, Gradwohl G, Nakanishi S, Guillemot F, Kageyama R (1999) Hes1 and Hes5 effectors in mammalian differentiation. Embo J 18:2196–2207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oishi K, Isazawa KS, Yoshimatsu Y, Kuida T, Nakafuku K, Masuyama N, Gotoh Y (2004) Notch promotes survival of neural precursor cells via mechanisms distinct from those regulating neurogenesis. Dev Biol 276:172–184

    Article  CAS  PubMed  Google Scholar 

  • Peng W, Vitvitskaia O, Carpenter D, Wechsler SL, Jones C (2008) Identification of two small RNAs within the first 1.5-kb of the herpes simplex virus type 1 (HSV-1) encoded latency-associated transcript (LAT). J Neurovirol 14:41–52

    Article  CAS  PubMed  Google Scholar 

  • Perng G-C, Jones C (2010) Towards an understanding of the herpes simplex virus type 1 latency-reactivation cycle. Interdiscipl Perspect Infect Dis 2010:1–18

    Google Scholar 

  • Perng G-C, Jones C, Ciacci-Zanella J, Stone M, Henderson G, Yukht A, Slanina SM, Hoffman FM, Ghiasi H, Nesburn AB, Wechsler SL (2000) Virus-induced neuronal apoptosis blocked by the herpes simplex virus latency-associated transcript (LAT). Science 287:1500–1503

    Article  CAS  PubMed  Google Scholar 

  • Perng G-C, Maguen B, Jin L, Mott KR, Osorio N, Slanina SM, Yukht A, Ghiasi H, Nesburn AB, Inman M, Henderson G, Jones C, Wechsler SL (2002) A gene capable of blocking apoptosis can substitute for the herpes simplex virus type 1 latency-associated transcript gene and restore wild-type reactivation levels. J Virol 76:1224–1235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raff MC, Whitmore AV, Finn JT (2002) Axonal self-destruction and neurodegeneration. Science 296:868–871

    Article  CAS  PubMed  Google Scholar 

  • Rock DL, Beam SL, Mayfield JE (1987) Mapping bovine herpesvirus type 1 latency-related RNA in trigeminal ganglia of latently infected rabbits. J Virol 61:3827–3831

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rock D, Lokensgard J, Lewis T, Kutish G (1992) Characterization of dexamethasone-induced reactivation of latent bovine herpesvirus 1. J Virol 66:2484–2490

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sade H, Krishna S, Sarin A (2004) The anti-apoptotic effect of notch-1 requires p56lck-dependent, AKT/PKB-mediated signaling in T cells. J Biol Chem 279:2937–2944

    Article  CAS  PubMed  Google Scholar 

  • Sestan N, Artavanis-Tsakonas S, Rakic P (1999) Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science 286:741–746

    Article  CAS  PubMed  Google Scholar 

  • Sethi N, Kang Y (2011) Notch signalling cancer progression and bone metastasis. Br J Cancer 105:1805–1810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen W, Jones C (2008) Open reading frame 2, encoded by the latency-related gene of bovine herpesvirus 1, has antiapoptotic activity in transiently transfected neuroblastoma cells. J Virol 82:10940–10945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen W, Silva MS, Jaber T, Vitvitskaia O, Li S, Henderson G, Jones C (2009) Two small RNAs encoded within the first 1.5 kb of the herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) can inhibit productive infection, and cooperate to inhibit apoptosis. J Virol 90:9131–9139

    Article  Google Scholar 

  • Shih I-M, Wang T-L (2007) Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res 67:1879–1882

    Article  CAS  PubMed  Google Scholar 

  • Sinani D, Jones C (2011) Localization of sequences in a protein encoded by the latency related gene of bovine herpesvirus 1 (ORF2) that inhibits apoptosis and interferes with notch1 mediated trans-activation of the bICP0 promoter. J Virol 85:12124–12133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sinani D, Frizzo da Silva L, Jones C (2013) A bovine herpesvirus 1 protein expressed in latently infected neurons (ORF2) promotes neurite sprouting in the presence of activated notch1 or notch3. J Virol 87:1183–1192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sinani D, Liu Y, Jones C (2014) Analysis of a bovine herpesvirus 1 protein encoded by an alternatively spliced latency related (LR) RNA that is abundantly expressed in latently infected neurons. Virology 465:244–252

  • Swiatek PJ, Lindsdell CE, del Amo FF, Weinmaster G, Gridley T (1994) Notch1 is essential for postimplantation development in mice. Genes Dev 8:707–719

    Article  CAS  PubMed  Google Scholar 

  • Turin L, Russo S, Poli G (1999) BHV-1: new molecular approaches to control a common and widespread infection. Mol Med 5:261–284

    CAS  PubMed  PubMed Central  Google Scholar 

  • Valerie D, Fardoux P, Lacombe P, Monet M, Maciazek J, Krebs LK, Klonjkowski B, Berrou E, Mericskay M, Li Z, Tournier-Lasserve E, Gridley T, Joutel A (2004) Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Gene Dev 18:2730–2735

    Article  Google Scholar 

  • Wang T, Holt CM, Xu C, Ridley C, Jones R, Baron M, Trump D (2007) Notch 3 activation modulates growth behavior and cross talks to Wnt/TCF signalling pathway. Cell Signal 19:2458–2467

    Article  CAS  PubMed  Google Scholar 

  • Workman A, Sinani D, Pittayakhajonwut D, Jones C (2011) A protein (ORF2) encoded by the latency related gene of bovine herpesvirus 1 interacts with notch1 and notch3. J Virol 85:2536–2546

    Article  CAS  PubMed  Google Scholar 

  • Workman A, Eudy J, Smith L, Frizzo da Silva L, Sinani D, Bricker H, Cook E, Doster A, Jones C (2012) Cellular transcription factors induced in trigeminal ganglia during dexamethasone-induced reactivation from latency stimulate bovine herpesvirus 1 productive infection and certain viral promoters. J Virol 86:2459–2473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This research was supported by grants from the Nebraska Research Initiative and the USDA, Agriculture and Food Research Initiative Competitive Grants Program (2013–01041). A grant to the Nebraska Center for Virology (1P20RR15635), in particular, funding of the Microscopy Core facility has also supported certain studies. Parts of the studies in this manuscript were previously presented at the 2013 International Herpesvirus Workshop, July 20–24, Grand Rapids, MI, USA.

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  1. Clinton Jones

    Present address: Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Oklahoma State University, 157C McElroy Hall, Stillwater, OK, 74078, USA

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  1. School of Veterinary Medicine and Biomedical Sciences, Nebraska Center for Virology, Morisson Life Science Center, University of Nebraska, Lincoln, Lincoln, NE, 68583-0900, USA

    Yilin Liu & Clinton Jones

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Liu, Y., Jones, C. Regulation of Notch-mediated transcription by a bovine herpesvirus 1 encoded protein (ORF2) that is expressed in latently infected sensory neurons. J. Neurovirol. 22, 518–528 (2016). https://doi.org/10.1007/s13365-015-0394-3

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