Role of Tegument Proteins in Herpesvirus Assembly and Egress
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Protein Cell 2010, 1(11): 987–998 Protein & Cell DOI 10.1007/s13238-010-0120-0 REVIEW Role of tegument proteins in herpesvirus assembly and egress ✉ Haitao Guo1,2, Sheng Shen1,2, Lili Wang1,2, Hongyu Deng1 1 CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China 2 Graduate School of the Chinese Academy of Sciences, Beijing 100080, China ✉ Correspondence: [email protected] Received October 4, 2010 Accepted November 4, 2010 ABSTRACT human pathogens, including the Alphaherpesvirinae mem- bers herpes simplex virus type 1 (HSV-1), herpes simplex Morphogenesis and maturation of viral particles is an virus type 2 (HSV-2) and varicella zoster virus (VZV), the essential step of viral replication. An infectious herpes- Betaherpesvirinae members human cytomegalovirus viral particle has a multilayered architecture, and con- (HCMV), human herpesvirus type 6 (HHV-6) and human tains a large DNA genome, a capsid shell, a tegument and herpesvirus type 7 (HHV-7), and the Gammaherpesvirinae an envelope spiked with glycoproteins. Unique to members Epstein-Barr virus (EBV) and Kaposi’s sarcoma- herpesviruses, tegument is a structure that occupies associated herpesvirus (KSHV). HSV most commonly cause the space between the nucleocapsid and the envelope mucocutaneous infections, resulting in recurrent orolabial or and contains many virus encoded proteins called tegu- genital lesions (Roizman et al., 2007). HCMV infection is ment proteins. Historically the tegument has been responsible for approximately 8% of infectious mononucleo- described as an amorphous structure, but increasing sis cases and is also associated with inflammatory and evidence supports the notion that there is an ordered proliferative diseases (Söderberg-Nauclér, 2006; Steininger, addition of tegument during virion assembly, which is 2007). EBV and KSHV are associated with several malig- consistent with the important roles of tegument proteins nancies, such as Burkitt’s lymphoma and Kaposi’s sarcoma in the assembly and egress of herpesviral particles. In (Chang et al., 1994; Kutok and Wang, 2006). this review we first give an overview of the herpesvirus All members of the Herpesviridae family comprise two assembly and egress process. We then discuss the roles distinct stages in their life cycle: lytic replication and latency of selected tegument proteins in each step of the (Sunil-Chandra et al., 1992; Decker et al., 1996a, b; Dupin et process, i.e., primary envelopment, deenvelopment, al., 1999; Flaño et al., 2000). Members of the Alphaherpesvir- secondary envelopment and transport of viral particles. inae subfamily establish latency in neurons, members of the We also suggest key issues that should be addressed in Betaherpesvirinae subfamily establish latency in a range of the near future. nonneuronal cells, whereas members of Gammaherpesvir- inae subfamily members establish latency mainly in B and T KEYWORDS herpesvirus, tegument, assembly, lymphocytes. Latency provides the viruses with advantages egress, transport to escape host immune surveillance so as to establish lifelong persistent infection and thus contributes to transformation and INTRODUCTION development of malignancies. However, it is through lytic replication that viruses propagate and transmit among hosts The family Herpesviridae consists of three subfamilies to maintain viral reservoirs. Both viral latency and lytic including Alphaherpesvirinae, Betaherpesvirinae and Gam- replication play important roles in herpesvirus pathogenesis. maherpesvirinae whose members infect a broad range of All herpesvirions have a characteristic multilayered archi- animal species including mammals, birds and reptiles tecture (Fig. 1). An infectious virion contains a double- (Davison et al., 2009). Until now, more than 130 herpes- stranded DNA genome, an icosahedral capsid shell, a thick, viruses have been identified, among which there are eight proteinaceous tegument compartment, and a lipid bilayer © Higher Education Press and Springer-Verlag Berlin Heidelberg 2010 987 Protein & Cell Haitao Guo et al. proposed to explain this process, among which the most widely accepted is the envelopment-deenvelopment- reenvelopment model: capsid formation and viral DNA packaging in the nucleus, primary envelopment at the inner nuclear membrane and deenvelopment at the outer nuclear membrane, association with tegument proteins and second- ary envelopment (i.e., reenvelopment) in the cytoplasm, and budding of complete virions into Golgi body-derived compart- ments for egress via the cellular secretory pathway (Metten- leiter, 2002, 2004). In each stage of virion assembly and Figure 1. Diagram of herpesvirion structure. The virion egress, tegument proteins are found to play important roles. particle is approximately 200 nm in diameter. A linear double- There are also lines of evidence suggesting direct exit from stranded DNA genome is packaged within an icosahedral the nucleus of unenveloped nucleocapsids via enlarged capsid to form the nucleocapsid. The capsid is embedded in a nuclear pores or transport of perinuclear enveloped nucleo- matrix known as the tegument layer, which contains many virus capsids through a continuum of outer nuclear, rough ER and coded proteins. The tegument is itself surrounded by the envelope, a lipid membrane containing several viral glycopro- Golgi membranes (Wild et al., 2002; Leuzinger et al., 2005; teins. Wild et al., 2005, 2009). In this review, the functional roles of tegument proteins will be discussed in the context of the envelopment-deenvelopment-reenvelopment model of virion envelope spiked with glycoproteins (Rixon, 1993; Roizman assembly. and Pellett, 2001; Liu and Zhou, 2006; Dai et al., 2008). As a unique structure of herpesviruses, the tegument plays TEGUMENT PROTEINS important roles in multiple aspects of the viral life cycle, including translocation of nucleocapsids into the nucleus as Composition of tegument in all three Herpesviridae subfami- well as virion assembly and egress (Subak-Sharpe and lies has been studied. At least 26, 38 or 17 virus-encoded Dargan, 1998; Fuchs et al., 2002a). As components that are tegument components are recruited into an HSV-1, HCMV or carried into a host cell during viral infection, tegument proteins EBV virion, respectively (Johannsen et al., 2004; Varnum et can also transactivate the expression of viral immediate-early al., 2004; Zhu et al., 2005; Loret et al., 2008). Some of these genes and cellular genes as well as modulate, host signal proteins, such as pUL36, pUL47, pUL48 and pUL49, are transduction and innate immunity (Bresnahan and Shenk, classified as major, structurally significant components (Heine 2000; Castillo and Kowalik, 2002; Ishov et al., 2002; Zhu et et al., 1974), whereas some, such as vhs and the protein al., 2002). kinase pUL13, are minor but nonetheless important compo- Virion assembly and egress is an essential stage of nents (Schek and Bachenheimer, 1985; Overton et al., 1992). herpesviral lytic replication, hence contributes indirectly to Some tegument proteins are conserved in all herpesvirus herpesvirus pathogenesis. In this review we summarize the members (Table 1), and their functions are progressively growing range of functions attributed to tegument proteins unrevealed. during the course of herpesvirus assembly and egress. We As an indispensable part of mature virion, tegument plays Alphaherpesvir- mainly focus on tegument proteins from the important roles in herpesviral particle production. Much effort inae subfamily, in particular HSV-1 and the related porcine has been placed on elucidating the molecular interactions pathogen pseudorabies virus (PrV), since they are the most between various tegument proteins with the hope of under- extensively studied. Meanwhile, some well studied tegument standing the mechanisms by which this complex virus is Betaherpesvirinae Gammaherpesvir- proteins from the and assembled. Tegument addition is thought to originate in the inae subfamilies are also discussed. nucleus, then more tegument proteins are added to capsids in the cytoplasm following nuclear egress and finally at trans- OVERVIEW OF HERPESVIRUS ASSEMBLY AND Golgi network (TGN)-derived membranes during maturation EGRESS budding (Mettenleiter, 2006). The complexity of virion assembly route clearly raises the issue that different tegu- During herpesvirus lytic infection, after attachment and ment proteins may be incorporated into herpesviral particles penetration, capsids are transported to the nucleus via at different stages of egress and that the composition of interaction with microtubules, docking at the nuclear pore virions in the perinuclear space may not be the same as that where the viral genome is released into the nucleus (Döhner of the mature extracellular viruses. For example, the UL31 et al., 2002; Wolfstein et al., 2006), where transcription of viral and UL34 gene products of PrV are present in viral particles in immediate-early, early and late genes and genome replication the perinuclear space but are absent from virions at later take place. Then virion assembly and egress proceed from stages of assembly and mature virions (Fuchs et al., 2002c). the nucleus to the cytoplasm. Several models have been In contrast, the pUL36, pUL37, pUL46, pUL47, pUL48 and 988 © Higher Education Press and Springer-Verlag Berlin Heidelberg 2010 Role of tegument proteins in herpesvirus assembly and egress Protein & Cell Table 1 Conservation of herpesvirus tegument proteins (capsid)-pUL36 (tegument),