RESEARCH ARTICLE

Murine gammaherpesvirus-68 ORF38 encodes a tegument protein and is packaged into virions during secondary envelopment

  • Sheng Shen 1,2 ,
  • Haitao Guo 1,2 ,
  • Hongyu Deng , 1
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  • 1. Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
  • 2. University of Chinese Academy of Sciences, Beijing 100049, China

Received date: 04 Feb 2013

Accepted date: 17 Apr 2013

Published date: 01 Feb 2014

Copyright

2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Tegument is the unique structure of a herpesvirion which occupies the space between nucleocapsid and envelope. Accumulating data have indicated that interactions among tegument proteins play a key role in virion morphogenesis. Morphogenesis of gammaherpesviruses including Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) is poorly understood due to the lack of efficient de novo lytic replication in cell culture. Murine gammaherpesvirus-68 (MHV-68) is genetically related to these two human herpesviruses and serves as an effective model to study the lytic replication of gammaherpesviruses. We previously showed that ORF33 of MHV-68 encodes a tegument protein and plays an essential role in virion maturation in the cytoplasm. However, the molecular mechanism of how ORF33 participates in virion morphogenesis has not been elucidated. In this study we demonstrated that ORF38 of MHV-68 is also a tegument protein and is localized to cytoplasmic compartments during both transient transfection and viral infection. Immuno-gold labeling assay showed that ORF38 is only present on virions that have entered the cytoplasmic vesicles, indicating that ORF38 is packaged into virions during secondary envelopment. We further showed that ORF38 co-localizes with ORF33 during viral infection; therefore, the interaction between ORF38 and ORF33 is conserved among herpesviruses. Notably, we found that although ORF33 by itself is distributed in both the nucleus and the cytoplasm, in the presence of ORF38, ORF33 is co-localized to trans-Golgi network (TGN), a site where secondary envelopment takes place.

Cite this article

Sheng Shen , Haitao Guo , Hongyu Deng . Murine gammaherpesvirus-68 ORF38 encodes a tegument protein and is packaged into virions during secondary envelopment[J]. Protein & Cell, 2014 , 5(2) : 141 -150 . DOI: 10.1007/s13238-013-0005-0

1
BainesJD, RoizmanB (1992) The UL11 gene of herpes simplex virus 1 encodes a function that facilitates nucleocapsid envelopment and egress from cells. J Virol66: 5168-5174

2
BaisC, SantomassoB, CosoO, ArvanitakisL, RaakaEG, GutkindJS, AschAS, CesarmanE, GershengornMC, MesriEA (1998) G-protein-coupled receptor of Kaposi’s sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature391: 86-89

DOI

3
BlackmanMA, FlanoE (2002) Persistent gamma-herpesvirus infections: what can we learn from an experimental mouse model?J Exp Med195: F29-F32

DOI

4
BortzE, WhiteleggeJP, JiaQ, ZhouZH, StewartJP, WuTT, SunR (2003) Identiflcation of proteins associated with murine gammaherpesvirus 68 virions. J Virol77: 13425-13432

DOI

5
BortzE, WangL, JiaQ, WuTT, WhiteleggeJP, DengH, ZhouZH, SunR (2007) Murine gammaherpesvirus 68 ORF52 encodes a tegument protein required for virion morphogenesis in the cytoplasm. J Virol81: 10137-10150

DOI

6
ChiuYF, SugdenB, ChangPJ, ChenLW, LinYJ, LanYC, LaiCH, LiouJY, LiuST, HungCH (2012) Characterization and intracellular trafflcking of Epstein-Barr virus BBLF1, a protein involved in virion maturation. J Virol86: 9647-9655

DOI

7
DaiW, JiaQ, BortzE, ShahS, LiuJ, AtanasovI, LiX, TaylorKA, SunR, ZhouZH (2008) Unique structures in a tumor herpesvirus revealed by cryo-electron tomography and microscopy. J Struct Biol161: 428-438

DOI

8
DeckerLL, KlamanLD, Thorley-LawsonDA (1996a) Detection of the latent form of Epstein-Barr virus DNA in the peripheral blood of healthy individuals. J Virol70: 3286-3289

9
DeckerLL, ShankarP, KhanG, FreemanRB, DezubeBJ, LiebermanJ, Thorley-LawsonDA (1996b) The Kaposi sarcoma-associated herpesvirus (KSHV) is present as an intact latent genome in KS tissue but replicates in the peripheral blood mononuclear cells of KS patients. J Exp Med184: 283-288

DOI

10
EfstathiouS, HoYM, HallS, StylesCJ, ScottSD, GompelsUA (1990) Murine herpesvirus 68 is genetically related to the gammaherpesviruses Epstein-Barr virus and herpesvirus saimiri. J Gen Virol71(Pt 6): 1365-1372

DOI

11
GanemD (2006) KSHV infection and the pathogenesis of Kaposi’s sarcoma. Annu Rev Pathol1: 273-296

DOI

12
GrundhoffA, GanemD (2004) Inefflcient establishment of KSHV latency suggests an additional role for continued lytic replication in Kaposi sarcoma pathogenesis. J Clin Invest113: 124-136

DOI

13
GuoH, WangL, PengL, ZhouZH, DengH (2009) Open reading frame 33 of a gammaherpesvirus encodes a tegument protein essential for virion morphogenesis and egress. J Virol83: 10582-10595

DOI

14
GuoH, ShenS, WangL, DengH (2010) Role of tegument proteins in herpesvirus assembly and egress. Protein Cell1: 987-998

DOI

15
JohannsenE, LuftigM, ChaseMR, WeickselS, Cahir-McFarlandE, IllanesD, SarracinoD, KieffE (2004) Proteins of purifled Epstein-Barr virus. Proc Natl Acad Sci USA101: 16286-16291

DOI

16
KattenhornLM, MillsR, WagnerM, LomsadzeA, MakeevV, BorodovskyM, PloeghHL, KesslerBM (2004) Identiflcation of proteins associated with murine cytomegalovirus virions. J Virol78: 11187-11197

DOI

17
KellyBJ, FraefelC, CunninghamAL, DiefenbachRJ (2009) Functional roles of the tegument proteins of herpes simplex virus type 1. Virus Res145: 173-186

DOI

18
KutokJL, WangF (2006) Spectrum of Epstein-Barr virus-associated diseases. Annu Rev Pathol1: 375-404

DOI

19
LeeS, SalwinskiL, ZhangC, ChuD, SampankanpanichC, ReyesNA, VangeloffA, XingF, LiX, WuTT et al (2011) An integrated approach to elucidate the intra-viral and viral-cellular protein interaction networks of a gamma-herpesvirus. PLoS Pathog7: e1002297

DOI

20
LoomisJS, BowzardJB, CourtneyRJ, WillsJW (2001) Intracellular trafflcking of the UL11 tegument protein of herpes simplex virus type 1. J Virol75: 12209-12219

DOI

21
LoretS, GuayG, LippeR (2008) Comprehensive characterization of extracellular herpes simplex virus type 1 virions. JVirol82: 8605-8618

DOI

22
MartinDF, KuppermannBD, WolitzRA, PalestineAG, LiH, RobinsonCA (1999) Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. Roche Ganciclovir Study Group. N Engl J Med340: 1063-1070

DOI

23
MettenleiterTC, KluppBG, GranzowH (2006) Herpesvirus assembly: a tale of two membranes. Curr Opin Microbiol9: 423-429

DOI

24
MettenleiterTC, KluppBG, GranzowH (2009) Herpesvirus assembly: an update. Virus Res143: 222-234

DOI

25
PhillipsSL, BresnahanWA (2012) The human cytomegalovirus (HCMV) tegument protein UL94 is essential for secondary envelopment of HCMV virions. J Virol86: 2523-2532

DOI

26
PhillipsSL, CygnarD, ThomasA, BresnahanWA (2012) Interaction between the human cytomegalovirus tegument proteins UL94 and UL99 is essential for virus replication. J Virol86: 9995-10005

DOI

27
RozenR, SathishN, LiY, YuanY (2008) Virion-wide protein interactions of Kaposi’s sarcoma-associated herpesvirus. J Virol82: 4742-4750

DOI

28
SanchezV, SztulE, BrittWJ (2000) Human cytomegalovirus pp28 (UL99) localizes to a cytoplasmic compartment which overlaps the endoplasmic reticulum-golgi-intermediate compartment. J Virol74: 3842-3851

DOI

29
SimasJP, EfstathiouS (1998) Murine gammaherpesvirus 68: a model for the study of gammaherpesvirus pathogenesis. Trends Microbiol6: 276-282

DOI

30
SoulierJ, GrolletL, OksenhendlerE, CacoubP, Cazals-HatemD, BabinetP, d’AgayMF, ClauvelJP, RaphaelM, DegosL et al (1995) Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood86: 1276-1280

31
StevensonPG, EfstathiouS (2005) Immune mechanisms in murine gammaherpesvirus-68 infection. Viral Immunol18: 445-456

DOI

32
StineJT, WoodC, HillM, EppA, RaportCJ, SchweickartVL, EndoY, SasakiT, SimmonsG, BoshoffC et al (2000) KSHV-encoded CC chemokine vMIP-III is a CCR4 agonist, stimulates angiogenesis, and selectively chemoattracts TH2 cells. Blood95: 1151-1157

33
Sunil-ChandraNP, EfstathiouS, NashAA (1992) Murine gammaherpesvirus 68 establishes a latent infection in mouse B lymphocytes in vivo. J Gen Virol73(Pt 12): 3275-3279

DOI

34
UetzP, DongYA, ZeretzkeC, AtzlerC, BaikerA, BergerB, RajagopalaSV, RoupelievaM, RoseD, FossumE et al (2006) Herpesviral protein networks and their interaction with the human proteome. Science311: 239-242

DOI

35
WangL, GuoH, ReyesN, LeeS, BortzE, GuoF, SunR, TongL, DengH (2012) Distinct domains in ORF52 tegument protein mediate essential functions in murine gammaherpesvirus 68 virion tegumentation and secondary envelopment. J Virol86: 1348-1357

DOI

36
WuTT, UsherwoodEJ, StewartJP, NashAA, SunR (2000) Rta of murine gammaherpesvirus 68 reactivates the complete lytic cycle from latency. J Virol74: 3659-3667

DOI

37
YehPC, MeckesDG Jr, WillsJW (2008) Analysis of the interaction between the UL11 and UL16 tegument proteins of herpes simplex virus. J Virol82: 10693-10700

DOI

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