Downloads

https://doi.org/10.53941/hm.2025.100006
He, H.-P., Liao, S., Gu, D.-D., Shi, K., & Gao, S. Structural Overview of Herpesvirus Tegument Proteins. Health and Metabolism. 2025. doi: https://doi.org/10.53941/hm.2025.100006
Volume 2, Issue 1, 2025
Copyright (c) 2025 by the authors.
Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Review

Structural Overview of Herpesvirus Tegument Proteins

Hui-Ping He 1,2,*, Shuang Liao 2, Dong-Dong Gu 2, Kun Shi 1, and Song Gao 2,*

1 Department of Gynecology and Obstetrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China

2 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China

* Correspondence: hehp@sysucc.org.cn (H.-P.H.); gaosong@sysucc.org.cn (S.G.)

Received: 14 November 2024; Revised: 10 December 2024; Accepted: 22 January 2025; Published: 14 February 2025

Abstract: Herpesviridae is a family of enveloped double-stranded DNA viruses that cause various diseases in hosts. Among the various components of herpesvirus particles, tegument proteins located between the envelope and nucleocapsid play crucial roles in viral replication, immune evasion, and host-pathogen interactions. Structural studies have unveiled the molecular architecture of tegument proteins, identifying conserved regions and functional domains that serve as therapeutic targets. For example, the immunogenic properties of pp150 have facilitated the development of HCMV vaccines, while structural insights into the BBRF2-BSRF1 complex have guided the design of inhibitors targeting hydrophobic interaction sites essential for viral envelopment. Understanding the three-dimensional structure of herpesvirus tegument proteins would reveal the molecular mechanism underlying the crosstalk with other viral and cellular components, necessitating research into their biological and pathological functions. In this review, we summarize current knowledge on the structural features of herpesvirus tegument proteins, highlighting the structure-based functional implications, including their potential as targets for antiviral drug development.

Keywords:

Herpesviridae tegument proteins structural studies antiviral targets

References

  1. Dunmire, S.K.; Hogquist, K.A.; Balfour, H.H. Infectious Mononucleosis. Curr. Top. Microbiol. Immunol. 2015, 390, 211–240. https://doi.org/10.1007/978-3-319-22822-8_9.
  2. Murata, T.; Tsurumi, T. Switching of EBV cycles between latent and lytic states. Rev. Med. Virol. 2014, 24, 142–153. https://doi.org/10.1002/rmv.1780.
  3. Klupp, B.G.; Fuchs, W.; Granzow, H.; Nixdorf, R.; Mettenleiter, T.C. Pseudorabies virus UL36 tegument protein physically interacts with the UL37 protein. J. Virol. 2002, 76, 3065–3071. https://doi.org/10.1128/jvi.76.6.3065-3071.2002.
  4. Whitehurst, C.B.; Vaziri, C.; Shackelford, J.; Pagano, J.S. Epstein-Barr virus BPLF1 deubiquitinates PCNA and attenuates polymerase eta recruitment to DNA damage sites. J. Virol. 2012, 86, 8097–8106. https://doi.org/10.1128/JVI.00588-12.
  5. Xu, H.; Su, C.; Pearson, A.; Mody, C.H.; Zheng, C. Herpes Simplex Virus 1 UL24 Abrogates the DNA Sensing Signal Pathway by Inhibiting NF-kappaB Activation. J. Virol. 2017, 91, e00025-17. https://doi.org/10.1128/JVI.00025-17.
  6. Murata, T. Encyclopedia of EBV-Encoded Lytic Genes: An Update. Adv. Exp. Med. Biol. 2018, 1045, 395–412. https://doi.org/10.1007/978-981-10-7230-7_18.
  7. Connolly, S.A.; Jardetzky, T.S.; Longnecker, R. The structural basis of herpesvirus entry. Nat. Rev. Microbiol. 2021, 19, 110–121. https://doi.org/10.1038/s41579-020-00448-w.
  8. Dai, X.; Gong, D.; Lim, H.; Jih, J.; Wu, T.T.; Sun, R.; Zhou, Z.H. Structure and mutagenesis reveal essential capsid protein interactions for KSHV replication. Nature 2018, 553, 521–525. https://doi.org/10.1038/nature25438.
  9. Dai, X.; Zhou, Z.H. Structure of the herpes simplex virus 1 capsid with associated tegument protein complexes. Science 2018, 360, eaao7298. https://doi.org/10.1126/science.aao7298.
  10. Li, Z.; Zhang, X.; Dong, L.; Pang, J.; Xu, M.; Zhong, Q.; Zeng, M.S.; Yu, X. CryoEM structure of the tegumented capsid of Epstein-Barr virus. Cell Res. 2020, 30, 873–884. https://doi.org/10.1038/s41422-020-0363-0.
  11. Liu, Y.T.; Jih, J.; Dai, X.; Bi, G.Q.; Zhou, Z.H. Cryo-EM structures of herpes simplex virus type 1 portal vertex and packaged genome. Nature 2019, 570, 257–261. https://doi.org/10.1038/s41586-019-1248-6.
  12. Yu, X.; Jih, J.; Jiang, J.; Zhou, Z.H. Atomic structure of the human cytomegalovirus capsid with its securing tegument layer of pp150. Science 2017, 356, eaam6892. https://doi.org/10.1126/science.aam6892.
  13. He, H.P.; Luo, M.; Cao, Y.L.; Lin, Y.X.; Zhang, H.; Zhang, X.; Ou, J.Y.; Yu, B.; Chen, X.; Xu, M.; et al. Structure of Epstein-Barr virus tegument protein complex BBRF2-BSRF1 reveals its potential role in viral envelopment. Nat. Commun. 2020, 11, 5405. https://doi.org/10.1038/s41467-020-19259-x.
  14. Ortiz, D.A.; Glassbrook, J.E.; Pellett, P.E. Protein-Protein Interactions Suggest Novel Activities of Human Cytomegalovirus Tegument Protein pUL103. J. Virol. 2016, 90, 7798–7810. https://doi.org/10.1128/JVI.00097-16.
  15. Roller, R.J.; Fetters, R. The herpes simplex virus 1 UL51 protein interacts with the UL7 protein and plays a role in its recruitment into the virion. J. Virol. 2015, 89, 3112–3122. https://doi.org/10.1128/JVI.02799-14.
  16. Koppen-Rung, P.; Dittmer, A.; Bogner, E. Intracellular Distribution of Capsid-Associated pUL77 of Human Cytomegalovirus and Interactions with Packaging Proteins and pUL93. J. Virol. 2016, 90, 5876–5885. https://doi.org/10.1128/JVI.00351-16.
  17. Preston, V.G.; Murray, J.; Preston, C.M.; McDougall, I.M.; Stow, N.D. The UL25 gene product of herpes simplex virus type 1 is involved in uncoating of the viral genome. J. Virol. 2008, 82, 6654–6666. https://doi.org/10.1128/JVI.00257-08.
  18. Jambunathan, N.; Chouljenko, D.; Desai, P.; Charles, A.S.; Subramanian, R.; Chouljenko, V.N.; Kousoulas, K.G. Herpes simplex virus 1 protein UL37 interacts with viral glycoprotein gK and membrane protein UL20 and functions in cytoplasmic virion envelopment. J. Virol. 2014, 88, 5927–5935. https://doi.org/10.1128/JVI.00278-14.
  19. Pasdeloup, D.; McElwee, M.; Beilstein, F.; Labetoulle, M.; Rixon, F.J. Herpesvirus tegument protein pUL37 interacts with dystonin/BPAG1 to promote capsid transport on microtubules during egress. J. Virol. 2013, 87, 2857–2867. https://doi.org/10.1128/JVI.02676-12.
  20. AuCoin, D.P.; Smith, G.B.; Meiering, C.D.; Mocarski, E.S. Betaherpesvirus-conserved cytomegalovirus tegument protein ppUL32 (pp150) controls cytoplasmic events during virion maturation. J. Virol. 2006, 80, 8199–8210. https://doi.org/10.1128/JVI.00457-06.
  21. Sen, J.; Liu, X.; Roller, R.; Knipe, D.M. Herpes simplex virus US3 tegument protein inhibits Toll-like receptor 2 signaling at or before TRAF6 ubiquitination. Virology 2013, 439, 65–73. https://doi.org/10.1016/j.virol.2013.01.026.
  22. Yao, X.D.; Rosenthal, K.L. Herpes simplex virus type 2 virion host shutoff protein suppresses innate dsRNA antiviral pathways in human vaginal epithelial cells. J. Gen. Virol. 2011, 92, 1981–1993. https://doi.org/10.1099/vir.0.030296-0.
  23. Landini, M.P.; Ripalti, A.; Sra, K.; Pouletty, P. Human cytomegalovirus structural proteins: Immune reaction against pp150 synthetic peptides. J. Clin. Microbiol. 1991, 29, 1868–1872. https://doi.org/10.1128/jcm.29.9.1868-1872.1991.
  24. Lui, W.Y.; Bharti, A.; Wong, N.M.; Jangra, S.; Botelho, M.G.; Yuen, K.S.; Jin, D.Y. Suppression of cGAS- and RIG-I-mediated innate immune signaling by Epstein-Barr virus deubiquitinase BPLF1. PLoS Pathog. 2023, 19, e1011186. https://doi.org/10.1371/journal.ppat.1011186.
  25. Albecka, A.; Owen, D.J.; Ivanova, L.; Brun, J.; Liman, R.; Davies, L.; Ahmed, M.F.; Colaco, S.; Hollinshead, M.; Graham, S.C.; et al. Dual Function of the pUL7-pUL51 Tegument Protein Complex in Herpes Simplex Virus 1 Infection. J. Virol. 2017, 91, e02196-16. https://doi.org/10.1128/JVI.02196-16.
  26. Fuchs, W.; Granzow, H.; Klopfleisch, R.; Klupp, B.G.; Rosenkranz, D.; Mettenleiter, T.C. The UL7 gene of pseudorabies virus encodes a nonessential structural protein which is involved in virion formation and egress. J. Virol. 2005, 79, 11291–11299. https://doi.org/10.1128/JVI.79.17.11291-11299.2005.
  27. Nozawa, N.; Kawaguchi, Y.; Tanaka, M.; Kato, A.; Kato, A.; Kimura, H.; Nishiyama, Y. Herpes simplex virus type 1 UL51 protein is involved in maturation and egress of virus particles. J. Virol. 2005, 79, 6947–6956. https://doi.org/10.1128/JVI.79.11.6947-6956.2005.
  28. Roller, R.J.; Haugo, A.C.; Yang, K.; Baines, J.D. The herpes simplex virus 1 UL51 gene product has cell type-specific functions in cell-to-cell spread. J. Virol. 2014, 88, 4058–4068. https://doi.org/10.1128/JVI.03707-13.
  29. Tanaka, M.; Sata, T.; Kawaguchi, Y. The product of the Herpes simplex virus 1 UL7 gene interacts with a mitochondrial protein, adenine nucleotide translocator 2. Virol. J. 2008, 5, 125. https://doi.org/10.1186/1743-422X-5-125.
  30. Xu, X.; Fan, S.; Zhou, J.; Zhang, Y.; Che, Y.; Cai, H.; Wang, L.; Guo, L.; Liu, L.; Li, Q. The mutated tegument protein UL7 attenuates the virulence of herpes simplex virus 1 by reducing the modulation of alpha-4 gene transcription. Virol. J. 2016, 13, 152. https://doi.org/10.1186/s12985-016-0600-9.
  31. Ahlqvist, J.; Mocarski, E. Cytomegalovirus UL103 controls virion and dense body egress. J. Virol. 2011, 85, 5125–5135. https://doi.org/10.1128/JVI.01682-10.
  32. Schauflinger, M.; Fischer, D.; Schreiber, A.; Chevillotte, M.; Walther, P.; Mertens, T.; von Einem, J. The tegument protein UL71 of human cytomegalovirus is involved in late envelopment and affects multivesicular bodies. J. Virol. 2011, 85, 3821–3832. https://doi.org/10.1128/JVI.01540-10.
  33. Yanagi, Y.; Masud, H.; Watanabe, T.; Sato, Y.; Goshima, F.; Kimura, H.; Murata, T. Initial Characterization of the Epstein(-)Barr Virus BSRF1 Gene Product. Viruses 2019, 11, 285. https://doi.org/10.3390/v11030285.
  34. Butt, B.G.; Owen, D.J.; Jeffries, C.M.; Ivanova, L.; Hill, C.H.; Houghton, J.W.; Ahmed, M.F.; Antrobus, R.; Svergun, D.I.; Welch, J.J.; et al. Insights into herpesvirus assembly from the structure of the pUL7:pUL51 complex. Elife 2020, 9, e53789. https://doi.org/10.7554/eLife.53789.
  35. Oda, S.; Arii, J.; Koyanagi, N.; Kato, A.; Kawaguchi, Y. The Interaction between Herpes Simplex Virus 1 Tegument Proteins UL51 and UL14 and Its Role in Virion Morphogenesis. J. Virol. 2016, 90, 8754–8767. https://doi.org/10.1128/JVI.01258-16.
  36. Meissner, C.S.; Suffner, S.; Schauflinger, M.; von Einem, J.; Bogner, E. A leucine zipper motif of a tegument protein triggers final envelopment of human cytomegalovirus. J. Virol. 2012, 86, 3370–3382. https://doi.org/10.1128/JVI.06556-11.
  37. Nozawa, N.; Daikoku, T.; Koshizuka, T.; Yamauchi, Y.; Yoshikawa, T.; Nishiyama, Y. Subcellular localization of herpes simplex virus type 1 UL51 protein and role of palmitoylation in Golgi apparatus targeting. J. Virol. 2003, 77, 3204–3216. https://doi.org/10.1128/jvi.77.5.3204-3216.2003.
  38. Evilevitch, A.; Sae-Ueng, U. Mechanical Capsid Maturation Facilitates the Resolution of Conflicting Requirements for Herpesvirus Assembly. J. Virol. 2022, 96, e0183121. https://doi.org/10.1128/JVI.01831-21.
  39. McNab, A.R.; Desai, P.; Person, S.; Roof, L.L.; Thomsen, D.R.; Newcomb, W.W.; Brown, J.C.; Homa, F.L. The product of the herpes simplex virus type 1 UL25 gene is required for encapsidation but not for cleavage of replicated viral DNA. J. Virol. 1998, 72, 1060–1070. https://doi.org/10.1128/JVI.72.2.1060-1070.1998.
  40. Bowman, B.R.; Welschhans, R.L.; Jayaram, H.; Stow, N.D.; Preston, V.G.; Quiocho, F.A. Structural characterization of the UL25 DNA-packaging protein from herpes simplex virus type 1. J. Virol. 2006, 80, 2309–2317. https://doi.org/10.1128/JVI.80.5.2309-2317.2006.
  41. Thurlow, J.K.; Murphy, M.; Stow, N.D.; Preston, V.G. Herpes simplex virus type 1 DNA-packaging protein UL17 is required for efficient binding of UL25 to capsids. J. Virol. 2006, 80, 2118–2126. https://doi.org/10.1128/JVI.80.5.2118-2126.2006.
  42. Toropova, K.; Huffman, J.B.; Homa, F.L.; Conway, J.F. The herpes simplex virus 1 UL17 protein is the second constituent of the capsid vertex-specific component required for DNA packaging and retention. J. Virol. 2011, 85, 7513–7522. https://doi.org/10.1128/JVI.00837-11.
  43. Ali, M.A.; Forghani, B.; Cantin, E.M. Characterization of an essential HSV-1 protein encoded by the UL25 gene reported to be involved in virus penetration and capsid assembly. Virology 1996, 216, 278–283. https://doi.org/10.1006/viro.1996.0061.
  44. Meissner, C.S.; Koppen-Rung, P.; Dittmer, A.; Lapp, S.; Bogner, E. A "coiled-coil" motif is important for oligomerization and DNA binding properties of human cytomegalovirus protein UL77. PLoS ONE 2011, 6, e25115. https://doi.org/10.1371/journal.pone.0025115.
  45. Dai, X.; Gong, D.; Wu, T.T.; Sun, R.; Zhou, Z.H. Organization of capsid-associated tegument components in Kaposi's sarcoma-associated herpesvirus. J. Virol. 2014, 88, 12694–12702. https://doi.org/10.1128/JVI.01509-14.
  46. Grzesik, P.; MacMath, D.; Henson, B.; Prasad, S.; Joshi, P.; Desai, P.J. Incorporation of the Kaposi's sarcoma-associated herpesvirus capsid vertex-specific component (CVSC) into self-assembled capsids. Virus Res. 2017, 236, 9–13. https://doi.org/10.1016/j.virusres.2017.04.016.
  47. Naniima, P.; Naimo, E.; Koch, S.; Curth, U.; Alkharsah, K.R.; Stroh, L.J.; Binz, A.; Beneke, J.M.; Vollmer, B.; Boning, H.; et al. Assembly of infectious Kaposi's sarcoma-associated herpesvirus progeny requires formation of a pORF19 pentamer. PLoS Biol. 2021, 19, e3001423. https://doi.org/10.1371/journal.pbio.3001423.
  48. Liu, W.; Cui, Y.; Wang, C.; Li, Z.; Gong, D.; Dai, X.; Bi, G.Q.; Sun, R.; Zhou, Z.H. Structures of capsid and capsid-associated tegument complex inside the Epstein-Barr virus. Nat. Microbiol. 2020, 5, 1285–1298. https://doi.org/10.1038/s41564-020-0758-1.
  49. Heming, J.D.; Conway, J.F.; Homa, F.L. Herpesvirus Capsid Assembly and DNA Packaging. Adv. Anat. Embryol. Cell Biol. 2017, 223, 119–142. https://doi.org/10.1007/978-3-319-53168-7_6.
  50. Draganova, E.B.; Zhang, J.; Zhou, Z.H.; Heldwein, E.E. Structural basis for capsid recruitment and coat formation during HSV-1 nuclear egress. Elife 2020, 9, e56627. https://doi.org/10.7554/eLife.56627.
  51. Desai, P.J. A null mutation in the UL36 gene of herpes simplex virus type 1 results in accumulation of unenveloped DNA-filled capsids in the cytoplasm of infected cells. J. Virol. 2000, 74, 11608–11618. https://doi.org/10.1128/jvi.74.24.11608-11618.2000.
  52. Zhao, J.; Zeng, Y.; Xu, S.; Chen, J.; Shen, G.; Yu, C.; Knipe, D.; Yuan, W.; Peng, J.; Xu, W.; et al. A Viral Deamidase Targets the Helicase Domain of RIG-I to Block RNA-Induced Activation. Cell Host Microbe 2016, 20, 770–784. https://doi.org/10.1016/j.chom.2016.10.011.
  53. Zhang, J.; Zhao, J.; Xu, S.; Li, J.; He, S.; Zeng, Y.; Xie, L.; Xie, N.; Liu, T.; Lee, K.; et al. Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication. Cell Host Microbe 2018, 24, 234–248 e235. https://doi.org/10.1016/j.chom.2018.07.004.
  54. Bechtel, J.T.; Shenk, T. Human cytomegalovirus UL47 tegument protein functions after entry and before immediate-early gene expression. J. Virol. 2002, 76, 1043–1050. https://doi.org/10.1128/jvi.76.3.1043-1050.2002.
  55. Tullman, J.A.; Harmon, M.E.; Delannoy, M.; Gibson, W. Recovery of an HMWP/hmwBP (pUL48/pUL47) complex from virions of human cytomegalovirus: Subunit interactions, oligomer composition, and deubiquitylase activity. J. Virol. 2014, 88, 8256–8267. https://doi.org/10.1128/JVI.00971-14.
  56. Masud, H.; Watanabe, T.; Sato, Y.; Goshima, F.; Kimura, H.; Murata, T. The BOLF1 gene is necessary for effective Epstein-Barr viral infectivity. Virology 2019, 531, 114–125. https://doi.org/10.1016/j.virol.2019.02.015.
  57. Boyle, J.P.; Monie, T.P. Computational analysis predicts the Kaposi's sarcoma-associated herpesvirus tegument protein ORF63 to be alpha helical. Proteins 2012, 80, 2063–2070. https://doi.org/10.1002/prot.24097.
  58. Koenigsberg, A.L.; Heldwein, E.E. Crystal Structure of the N-Terminal Half of the Traffic Controller UL37 from Herpes Simplex Virus 1. J. Virol. 2017, 91, e01244-17. https://doi.org/10.1128/JVI.01244-17.
  59. Sugimoto, A.; Yamashita, Y.; Kanda, T.; Murata, T.; Tsurumi, T. Epstein-Barr virus genome packaging factors accumulate in BMRF1-cores within viral replication compartments. PLoS ONE 2019, 14, e0222519. https://doi.org/10.1371/journal.pone.0222519.
  60. Whitehurst, C.B.; Ning, S.; Bentz, G.L.; Dufour, F.; Gershburg, E.; Shackelford, J.; Langelier, Y.; Pagano, J.S. The Epstein-Barr virus (EBV) deubiquitinating enzyme BPLF1 reduces EBV ribonucleotide reductase activity. J. Virol. 2009, 83, 4345–4353. https://doi.org/10.1128/JVI.02195-08.
  61. Trus, B.L.; Newcomb, W.W.; Cheng, N.; Cardone, G.; Marekov, L.; Homa, F.L.; Brown, J.C.; Steven, A.C. Allosteric signaling and a nuclear exit strategy: Binding of UL25/UL17 heterodimers to DNA-Filled HSV-1 capsids. Mol. Cell 2007, 26, 479–489. https://doi.org/10.1016/j.molcel.2007.04.010.
  62. Yang, C.; Tang, D.; Atluri, S. Patient-Specific Carotid Plaque Progression Simulation Using 3D Meshless Generalized Finite Difference Models with Fluid-Structure Interactions Based on Serial In Vivo MRI Data. Comput. Model. Eng. Sci. 2011, 72, 53–77.
  63. Newcomb, W.W.; Brown, J.C. Structure and capsid association of the herpesvirus large tegument protein UL36. J. Virol. 2010, 84, 9408–9414. https://doi.org/10.1128/JVI.00361-10.
  64. Liu, Y.T.; Strugatsky, D.; Liu, W.; Zhou, Z.H. Structure of human cytomegalovirus virion reveals host tRNA binding to capsid-associated tegument protein pp150. Nat. Commun. 2021, 12, 5513. https://doi.org/10.1038/s41467-021-25791-1.
  65. Han, J.; Chadha, P.; Starkey, J.L.; Wills, J.W. Function of glycoprotein E of herpes simplex virus requires coordinated assembly of three tegument proteins on its cytoplasmic tail. Proc. Natl. Acad. Sci. U S A 2012, 109, 19798–19803. https://doi.org/10.1073/pnas.1212900109.
  66. Harper, A.L.; Meckes, D.G., Jr.; Marsh, J.A.; Ward, M.D.; Yeh, P.C.; Baird, N.L.; Wilson, C.B.; Semmes, O.J.; Wills, J.W. Interaction domains of the UL16 and UL21 tegument proteins of herpes simplex virus. J. Virol. 2010, 84, 2963–2971. https://doi.org/10.1128/JVI.02015-09.
  67. Klupp, B.G.; Bottcher, S.; Granzow, H.; Kopp, M.; Mettenleiter, T.C. Complex formation between the UL16 and UL21 tegument proteins of pseudorabies virus. J. Virol. 2005, 79, 1510–1522. https://doi.org/10.1128/JVI.79.3.1510-1522.2005.
  68. Le Sage, V.; Jung, M.; Alter, J.D.; Wills, E.G.; Johnston, S.M.; Kawaguchi, Y.; Baines, J.D.; Banfield, B.W. The herpes simplex virus 2 UL21 protein is essential for virus propagation. J. Virol. 2013, 87, 5904–5915. https://doi.org/10.1128/JVI.03489-12.
  69. Sarfo, A.; Starkey, J.; Mellinger, E.; Zhang, D.; Chadha, P.; Carmichael, J.; Wills, J.W. The UL21 Tegument Protein of Herpes Simplex Virus 1 Is Differentially Required for the Syncytial Phenotype. J. Virol. 2017, 91, e01161-17. https://doi.org/10.1128/JVI.01161-17.
  70. Metrick, C.M.; Chadha, P.; Heldwein, E.E. The unusual fold of herpes simplex virus 1 UL21, a multifunctional tegument protein. J. Virol. 2015, 89, 2979–2984. https://doi.org/10.1128/JVI.03516-14.
  71. Curanovic, D.; Lyman, M.G.; Bou-Abboud, C.; Card, J.P.; Enquist, L.W. Repair of the UL21 locus in pseudorabies virus Bartha enhances the kinetics of retrograde, transneuronal infection in vitro and in vivo. J. Virol. 2009, 83, 1173–1183. https://doi.org/10.1128/JVI.02102-08.
  72. Klupp, B.G.; Lomniczi, B.; Visser, N.; Fuchs, W.; Mettenleiter, T.C. Mutations affecting the UL21 gene contribute to avirulence of pseudorabies virus vaccine strain Bartha. Virology 1995, 212, 466–473. https://doi.org/10.1006/viro.1995.1504.
  73. de Wind, N.; Wagenaar, F.; Pol, J.; Kimman, T.; Berns, A. The pseudorabies virus homology of the herpes simplex virus UL21 gene product is a capsid protein which is involved in capsid maturation. J. Virol. 1992, 66, 7096–7103. https://doi.org/10.1128/JVI.66.12.7096-7103.1992.
  74. Yang, L.; Wang, M.; Zeng, C.; Shi, Y.; Cheng, A.; Liu, M.; Zhu, D.; Chen, S.; Jia, R.; Yang, Q.; et al. Duck enteritis virus UL21 is a late gene encoding a protein that interacts with pUL16. BMC Vet. Res. 2020, 16, 8. https://doi.org/10.1186/s12917-019-2228-7.
  75. Takakuwa, H.; Goshima, F.; Koshizuka, T.; Murata, T.; Daikoku, T.; Nishiyama, Y. Herpes simplex virus encodes a virion-associated protein which promotes long cellular processes in over-expressing cells. Genes. Cells 2001, 6, 955–966. https://doi.org/10.1046/j.1365-2443.2001.00475.x.
  76. Metrick, C.M.; Heldwein, E.E. Novel Structure and Unexpected RNA-Binding Ability of the C-Terminal Domain of Herpes Simplex Virus 1 Tegument Protein UL21. J. Virol. 2016, 90, 5759–5769. https://doi.org/10.1128/JVI.00475-16.
  77. Leigh, K.E.; Sharma, M.; Mansueto, M.S.; Boeszoermenyi, A.; Filman, D.J.; Hogle, J.M.; Wagner, G.; Coen, D.M.; Arthanari, H. Structure of a herpesvirus nuclear egress complex subunit reveals an interaction groove that is essential for viral replication. Proc. Natl. Acad. Sci. USA 2015, 112, 9010–9015. https://doi.org/10.1073/pnas.1511140112.
  78. Sam, M.D.; Evans, B.T.; Coen, D.M.; Hogle, J.M. Biochemical, biophysical, and mutational analyses of subunit interactions of the human cytomegalovirus nuclear egress complex. J. Virol. 2009, 83, 2996–3006. https://doi.org/10.1128/JVI.02441-08.
  79. Milbradt, J.; Auerochs, S.; Sticht, H.; Marschall, M. Cytomegaloviral proteins that associate with the nuclear lamina: Components of a postulated nuclear egress complex. J. Gen. Virol. 2009, 90, 579–590. https://doi.org/10.1099/vir.0.005231-0.
  80. Sharma, M.; Kamil, J.P.; Coughlin, M.; Reim, N.I.; Coen, D.M. Human cytomegalovirus UL50 and UL53 recruit viral protein kinase UL97, not protein kinase C, for disruption of nuclear lamina and nuclear egress in infected cells. J. Virol. 2014, 88, 249–262. https://doi.org/10.1128/JVI.02358-13.
  81. Popa, M.; Ruzsics, Z.; Lotzerich, M.; Dolken, L.; Buser, C.; Walther, P.; Koszinowski, U.H. Dominant negative mutants of the murine cytomegalovirus M53 gene block nuclear egress and inhibit capsid maturation. J. Virol. 2010, 84, 9035–9046. https://doi.org/10.1128/JVI.00681-10.
  82. Lye, M.F.; Sharma, M.; El Omari, K.; Filman, D.J.; Schuermann, J.P.; Hogle, J.M.; Coen, D.M. Unexpected features and mechanism of heterodimer formation of a herpesvirus nuclear egress complex. EMBO J. 2015, 34, 2937–2952. https://doi.org/10.15252/embj.201592651.
  83. Adhikary, D.; Damaschke, J.; Mautner, J.; Behrends, U. The Epstein-Barr Virus Major Tegument Protein BNRF1 Is a Common Target of Cytotoxic CD4(+) T Cells. J. Virol. 2020, 94, 93–95. https://doi.org/10.1128/JVI.00284-20.
  84. Lieberman, P.M. Chromatin Structure of Epstein-Barr Virus Latent Episomes. Curr. Top. Microbiol. Immunol. 2015, 390, 71–102. https://doi.org/10.1007/978-3-319-22822-8_5.
  85. Schreiner, S.; Wodrich, H. Virion factors that target Daxx to overcome intrinsic immunity. J. Virol. 2013, 87, 10412–10422. https://doi.org/10.1128/JVI.00425-13.
  86. Huang, H.; Deng, Z.; Vladimirova, O.; Wiedmer, A.; Lu, F.; Lieberman, P.M.; Patel, D.J. Structural basis underlying viral hijacking of a histone chaperone complex. Nat. Commun. 2016, 7, 12707. https://doi.org/10.1038/ncomms12707.
  87. Tsai, K.; Messick, T.E.; Lieberman, P.M. Disruption of host antiviral resistances by gammaherpesvirus tegument proteins with homology to the FGARAT purine biosynthesis enzyme. Curr. Opin. Virol. 2015, 14, 30–40. https://doi.org/10.1016/j.coviro.2015.07.008.
  88. Cheng, A.Z.; Moraes, S.N.; Attarian, C.; Yockteng-Melgar, J.; Jarvis, M.C.; Biolatti, M.; Galitska, G.; Dell'Oste, V.; Frappier, L.; Bierle, C.J.; et al. A Conserved Mechanism of APOBEC3 Relocalization by Herpesviral Ribonucleotide Reductase Large Subunits. J. Virol. 2019, 93, e01539-19. https://doi.org/10.1128/JVI.01539-19.
  89. Cheng, A.Z.; Yockteng-Melgar, J.; Jarvis, M.C.; Malik-Soni, N.; Borozan, I.; Carpenter, M.A.; McCann, J.L.; Ebrahimi, D.; Shaban, N.M.; Marcon, E.; et al. Epstein-Barr virus BORF2 inhibits cellular APOBEC3B to preserve viral genome integrity. Nat. Microbiol. 2019, 4, 78–88. https://doi.org/10.1038/s41564-018-0284-6.
  90. Greene, B.L.; Kang, G.; Cui, C.; Bennati, M.; Nocera, D.G.; Drennan, C.L.; Stubbe, J. Ribonucleotide Reductases: Structure, Chemistry, and Metabolism Suggest New Therapeutic Targets. Annu. Rev. Biochem. 2020, 89, 45–75. https://doi.org/10.1146/annurev-biochem-013118-111843.
  91. Shaban, N.M.; Yan, R.; Shi, K.; Moraes, S.N.; Cheng, A.Z.; Carpenter, M.A.; McLellan, J.S.; Yu, Z.; Harris, R.S. Cryo-EM structure of the EBV ribonucleotide reductase BORF2 and mechanism of APOBEC3B inhibition. Sci. Adv. 2022, 8, eabm2827. https://doi.org/10.1126/sciadv.abm2827.
  92. Chen, J.; Lu, Z.; Gong, W.; Xiao, X.; Feng, X.; Li, W.; Shan, S.; Xu, D.; Zhou, Z. Epstein-Barr virus protein BKRF4 restricts nucleosome assembly to suppress host antiviral responses. Proc. Natl. Acad. Sci. USA 2022, 119, e2203782119. https://doi.org/10.1073/pnas.2203782119.
  93. Liu, Y.; Li, Y.; Bao, H.; Liu, Y.; Chen, L.; Huang, H. Epstein-Barr Virus Tegument Protein BKRF4 is a Histone Chaperone. J. Mol. Biol. 2022, 434, 167756. https://doi.org/10.1016/j.jmb.2022.167756.