The Product of the Herpes Simplex Virus Type 1 UL25 Gene Is Required for Encapsidation but Not for Cleavage of Replicated Viral DNA

McNab, Alistair R.; Desai, Prashant; Person, Stan; Roof, Lori L.; Thomsen, Darrell R.; Newcomb, William W.; Brown, Jay C.; Homa, Fred L.

doi:10.1128/jvi.72.2.1060-1070.1998

Cited by 163 publications

(84 citation statements)

References 53 publications

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“…The phenotype of the VP26 null mutation in nucleocapsid maturation observed in this study was similar to that of the UL25 null mutation, as previously reported (7,34). The UL25 null mutation (i) had no obvious effect on cleavage of replicated HSV-1 DNA concatemers, (ii) impaired packaging of viral DNA genomes, and (iii) accumulated type A capsids and reduced type C capsid formation in the nuclei of infected cells (7,34). Interestingly, of the HSV-1 regulators for viral DNA genome packaging, this phenotype is unique to UL25.…”

Section: Discussionsupporting

confidence: 90%

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Herpes Simplex Virus 1 Small Capsomere-Interacting Protein VP26 Regulates Nucleocapsid Maturation

Kobayashi

Sagara

Watanabe

et al. 2017

J Virol

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VP26 is a herpes simplex virus 1 (HSV-1) small capsomere-interacting protein. In this study, we investigated the function of VP26 in HSV-1-infected cells with the following results. (i) The VP26 null mutation significantly impaired incorporation of minor capsid protein UL25 into nucleocapsids (type C capsids) in the nucleus. (ii) The VP26 mutation caused improper localization of UL25 in discrete punctate domains containing multiple capsid proteins (e.g., the VP5 major capsid protein) in the nucleus; these domains corresponded to capsid aggregates. (iii) The VP26 mutation significantly impaired packaging of replicated viral DNA genomes into capsids but had no effect on viral DNA concatemer cleavage. (iv) The VP26 mutation reduced the frequency of type C capsids, which contain viral DNA but not scaffolding proteins, and produced an accumulation of type A capsids, which lack both viral DNA and scaffold proteins, and had no effect on accumulation of type B capsids, which lack viral DNA but retain cleaved scaffold proteins. Collectively, these results indicated that VP26 was required for efficient viral DNA packaging and proper localization of nuclear capsids. The phenotype of the VP26 null mutation was similar to that reported previously of the UL25 null mutation and of UL25 mutations that preclude UL25 binding to capsids. Thus, VP26 appeared to regulate nucleocapsid maturation by promoting incorporation of UL25 into capsids, which is likely to be required for proper capsid nuclear localization. HSV-1 VP26 has been reported to be important for viral replication and virulence in cell cultures and/or mouse models. However, little is known about the function of VP26 during HSV-1 replication, in particular, in viral nucleocapsid maturation although HSV-1 nucleocapsids are estimated to contain 900 copies of VP26. In this study, we present data suggesting that VP26 promoted packaging of HSV-1 DNA genomes into capsids by regulating incorporation of capsid protein UL25 into capsids, which was reported to increase stability of the capsid structure. We also showed that VP26 was required for proper localization of capsids in the infected cell nucleus. This is the first report showing that HSV-1 VP26 is a regulator for nucleocapsid maturation.

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Section: Discussionsupporting

confidence: 90%

“…The HSV-1 terminase cleaves nascent viral concatemeric DNA into unit-length viral genomes, docks at the capsid portal vertex, and packages a cleaved progeny virus genome into the capsid (3)(4)(5). In addition, the UL25 and UL17 components of CVSCs have been reported to be required for cleavage and/or packaging of nascent HSV-1 DNA genomes (6,7).…”

mentioning

confidence: 99%

Herpes Simplex Virus 1 Small Capsomere-Interacting Protein VP26 Regulates Nucleocapsid Maturation

Kobayashi

Sagara

Watanabe

et al. 2017

J Virol

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“…The capsid associated tegument complex (CATC – previously termed CCSC and CVSC), comprised of pUL17, pUL25 and pUL36 binds to the triplexes and hexons about the icosahedral five-fold vertices of mature capsids within the nucleus 16-21 . Notably, it has been observed that pUL25 is essential for retention of DNA within the nucleocapsid 22,23 . Moreover, pUL25 has also been shown to be important for genome release 24 .…”

Section: Introductionmentioning

confidence: 99%

Structure of the herpes-simplex virus portal-vertex

McElwee

Víjayakríshnan

Rixon

et al. 2018

Preprint

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Herpesviruses include many important human pathogens such as herpes simplex virus, cytomegalovirus, varicella-zoster virus and the oncogenic Epstein-Barr virus and Kaposi-sarcoma associated herpesvirus. Herpes virions contains large icosahedral capsids that have a portal at a unique five-fold vertex, similar to that seen in the tailed bacteriophages. The portal is a molecular motor through which the viral genome enters the capsid during virion morphogenesis. The genome also exits the capsid through the portal-vertex when it is injected through the nuclear-pore into the nucleus of a new host cell to initiate infection. Structural investigations of the herpesvirus portal-vertex have proven challenging, owing to the small size of the tail-like portal-vertex associated tegument (PVAT), and the dense tegument layer that lays between the nucleocapsid and the viral envelope, obscuring the view of the portal-vertex. Here we show the structure of the herpes simplex virus portal-vertex at sub-nanometer resolution, solved by electron cryomicroscopy (cryoEM) and single-particle 3D reconstruction. This led to a number of new discoveries including the presence of two previously unknown portal associated structures that occupy the sites normally taken by the penton and the Ta triplex. Our data revealed that the PVAT is composed of ten copies of the C-terminal domain of pUL25, which are uniquely arranged as two tiers of star-shaped density. Our 3D reconstruction of the portal-vertex also shows that one end of the viral genome extends outside the portal in the manner described for some bacteriophage but not previously seen in any eukaryote viruses. Finally, we show that the viral genome is consistently packed in a highly-ordered left-handed spool to form concentric shells of DNA. Our data provide new insights into the structure of a molecular machine critical to the biology of an important class of human pathogens.

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“…The translocation of concatenated viral DNA into procapsids and its cleavage at packaging sites is not understood. Recent studies with herpes simplex virus type 1 (HSV-1) mutants defective in UL6, UL15, UL25, UL28, UL32 or UL33 suggest that these genes are essentially involved in viral DNA cleavage and packaging, since cells infected with these mutants produce only B capsids lacking DNA (Al-Kobaisi et al 1991;Baines et al 1997;Weller 1996, 1998;McNab et al 1998;Patel et al 1996;Tengelsen et al 1993;Yu et al 1997). The respective homologues of these genes in HCMV are UL104, UL89, UL77, UL56, UL52 and UL51 (Chee et al 1990).…”

Section: Terminase Inhibitorsmentioning

confidence: 99%

Other Inhibitors of Viral Enzymes and Functions

Zimmermann

Hewlett²,

Rübsamen‐Waigmann

2009

Antiviral Strategies

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Until the end of the 1970s, the mainstays of antiviral chemotherapy were nucleoside analogues that targeted virus polymerase, in particular, the herpesvirus DNA polymerase. The scourge of HIV triggered an unprecedented commitment to identify novel antivirals, and these efforts transformed antiviral therapy into the modern, sophisticated treatment form described in this book, with targets such as the reverse transcriptase and the protease as well as the entry of the human immunodeficiency virus. As the regulation of human pathogenic virus growth cycles became more understandable, the realisation grew that these pathogens had more than one Achilles heel that might be suitable targets for small molecules with antiviral activity. This chapter addresses those "other" targets as well as other approaches to the tried and tested polymerase inhibitors, the so-called non-nucleoside inhibitors of reverse transcriptase.

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The Product of the Herpes Simplex Virus Type 1 UL25 Gene Is Required for Encapsidation but Not for Cleavage of Replicated Viral DNA

Cited by 163 publications

References 53 publications

Herpes Simplex Virus 1 Small Capsomere-Interacting Protein VP26 Regulates Nucleocapsid Maturation

Herpes Simplex Virus 1 Small Capsomere-Interacting Protein VP26 Regulates Nucleocapsid Maturation

Structure of the herpes-simplex virus portal-vertex

Other Inhibitors of Viral Enzymes and Functions

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