Simian virus 40 large T antigen host range domain functions in virion assembly

Spence, Susan L.; Pipas, James M.

doi:10.1128/jvi.68.7.4227-4240.1994

Cited by 27 publications

(4 citation statements)

References 65 publications

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“…SV40 host range virus defects have been reported at several distinct stages of the viral life cycle in restrictive cells, including early and late gene expression (22)(23)(24), DNA replication (18), and virion assembly and release (25). Here, we have shown that formation of viral replication centers is also severely impaired for SV40 host range mutants.…”

Section: Discussionmentioning

confidence: 55%

“…Host range (HR) mutants of SV40 with specific deletions in the C terminus of LT fail to replicate efficiently and do not form plaques in restrictive cell lines, such as African green monkey kidney CV-1P cells or the human osteosarcoma cell line U-2 OS (U2OS here) (18,21,22). Under restrictive conditions, host range mutant viruses exhibit impairment at multiple stages of the viral life cycle, including decreased early (LT) and late (VP1 and VP3) gene and protein expression (22)(23)(24), impaired viral DNA replication (18), and defective virion assembly (25). Additionally, host range SV40 mutants are defective for the adenovirus helper function and, unlike wild-type SV40, cannot support human adenovirus replication in monkey cells upon coinfection (20,26).…”

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confidence: 99%

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Contribution of DNA Replication to the FAM111A-Mediated Simian Virus 40 Host Range Phenotype

Tarnita

Wilkie

DeCaprio

2019

J Virol

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Host range (HR) mutants of simian virus 40 (SV40) containing mutations in the C terminus of large T antigen fail to replicate efficiently or form plaques in restrictive cell types. HR mutant viruses exhibit impairments at several stages of the viral life cycle, including early and late gene and protein expression, DNA replication, and virion assembly, although the underlying mechanism for these defects is unknown. Host protein FAM111A, whose depletion rescues early and late gene expression and plaque formation for SV40 HR viruses, has been shown to play a role in cellular DNA replication. SV40 viral DNA replication occurs in the nucleus of infected cells in viral replication centers where viral proteins and cellular replication factors localize. Here, we examined the role of viral replication center formation and DNA replication in the FAM111A-mediated HR phenotype. We found that SV40 HR virus rarely formed viral replication centers in restrictive cells, a phenotype that could be rescued by FAM111A depletion. Furthermore, while FAM111A localized to nucleoli in uninfected cells in a cell cycle-dependent manner, FAM111A relocalized to viral replication centers after infection with SV40 wild-type or HR viruses. We also found that inhibition of viral DNA replication through aphidicolin treatment or through the use of replication-defective SV40 mutants diminished the effects of FAM111A depletion on viral gene expression. These results indicate that FAM111A restricts SV40 HR viral replication center formation and that viral DNA replication contributes to the FAM111A-mediated effect on early gene expression.IMPORTANCESV40 has served as a powerful tool for understanding fundamental viral and cellular processes; however, despite extensive study, the SV40 HR mutant phenotype remains poorly understood. Mutations in the C terminus of large T antigen that disrupt binding to the host protein FAM111A render SV40 HR viruses unable to replicate in restrictive cell types. Our work reveals a defect of HR mutant viruses in the formation of viral replication centers that can be rescued by depletion of FAM111A. Furthermore, inhibition of viral DNA replication reduces the effects of FAM111A restriction on viral gene expression. Additionally, FAM111A is a poorly characterized cellular protein whose mutation leads to two severe human syndromes, Kenny-Caffey syndrome and osteocraniostenosis. Our findings regarding the role of FAM111A in restricting viral replication and its localization to nucleoli and viral replication centers provide further insight into FAM111A function that could help reveal the underlying disease-associated mechanisms.

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Section: Discussionmentioning

confidence: 55%

mentioning

confidence: 99%

Contribution of DNA Replication to the FAM111A-Mediated Simian Virus 40 Host Range Phenotype

Tarnita

Wilkie

DeCaprio

2019

J Virol

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“…In case of the first possibility, the 30S Rep-Cap complexes would implicate the involvement of Rep proteins and possibly of AAV DNA in the capsid assembly process. Recently the involvement of the simian virus 40 large T antigen in capsid assembly was demonstrated (35,36), and similar results were obtained for the polyomavirus middle T antigen (13)(14)(15). Although in these cases no direct association of the large or middle T antigen with the capsid protein oligomers has been demonstrated, it is tempting to speculate that AAV Rep proteins play a role in AAV capsid assembly.…”

Section: Downloaded Frommentioning

confidence: 64%

Intermediates of adeno-associated virus type 2 assembly: identification of soluble complexes containing Rep and Cap proteins

Wistuba

Weger

Kern

et al. 1995

J Virol

128

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The proteins encoded by the adeno-associated virus type 2 (AAV-2) rep and cap genes obtained during a productive infection of HeLa cells with AAV-2 and adenovirus type 2 were fractionated according to solubility, cellular localization, and sedimentation properties. The majority of Rep and Cap proteins accumulated in the nucleus, where they distributed into a soluble and an insoluble fraction. Analysis of the soluble nuclear fraction of capsid proteins by sucrose density gradients showed that they formed at least three steady-state pools: a monomer pool sedimenting at about 6S, a pool of oligomeric intermediates sedimenting between 10 and 15S, and a broad pool of assembly products with a peak between 60 and 110S, the known sedimentation positions of empty and full capsids. While the soluble nuclear monomer and oligomer pool contained predominantly only two capsid proteins, the 30 to 180S assembly products contained VP1, VP2, and VP3 in a stoichiometry similar to that of purified virions. They probably represent different intermediates in capsid assembly, DNA encapsidation, and capsid maturation. In contrast, the cytoplasmic fraction of capsid proteins showed a pattern of oligomers continuously increasing in size without a defined peak, suggesting that assembly of 60S particles occurs in the nucleus. Soluble nuclear Rep proteins were distributed over the whole sedimentation range, probably as a result of association with AAV DNA. Subfractions of the Rep proteins with defined sedimentation values were obtained in the soluble nuclear and cytoplasmic fractions. We were able to coimmunoprecipitate capsid proteins sedimenting between 60 and 110S with antibodies against Rep proteins, suggesting that they exist in common complexes possibly involved in AAV DNA packaging. Antibodies against the capsid proteins, however, precipitated Rep78 and Rep68 predominantly with a peak around 30S representing a second complex containing Rep and Cap proteins.

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“…Thus the deletion of the carboxyl‐terminal domain of T antigen affects both viral capsid protein synthesis and, through its action on agnoprotein, the assembly and maturation of virions (Stacy et al, 1989). Direct evidence for a defect in virion assembly and maturation in the C‐terminal T‐antigen mutants has been provided by sucrose density gradient analysis of virus‐infected cell extracts (Spence and Pipas, 1994). Intercistronic complementation of these mutants could be achieved with mutants of SV40 that were defective in agnoprotein but produced wild‐type T‐antigen.…”

Section: Early Studies Of the Role Of Sv40 Agnoprotein In The Viral Lmentioning

confidence: 99%

The agnoprotein of polyomaviruses: A multifunctional auxiliary protein

Khalili¹,

White²,

Sawa³

et al. 2004

Journal Cellular Physiology

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The late region of the three primate polyomaviruses (JCV, BKV, and SV40) encodes a small, highly basic protein known as agnoprotein. While much attention during the last two decades has focused on the transforming proteins encoded by the early region (small and large T-antigens), it has become increasingly evident that agnoprotein has a critical role in the regulation of viral gene expression and replication, and in the modulation of certain important host cell functions including cell cycle progression and DNA repair. The importance of agnoprotein is underscored by its expression during lytic infection of glial cells by JCV that occurs in progressive multifocal leukoencephalopathy (PML), and also in some JCV-associated human neural tumors particularly medulloblastoma. In this review, we will discuss the structure and function of agnoprotein in the viral life cycle during the course of lytic infection and the consequences of agnoprotein expression for the host cell.

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Simian virus 40 large T antigen host range domain functions in virion assembly

Cited by 27 publications

References 65 publications

Contribution of DNA Replication to the FAM111A-Mediated Simian Virus 40 Host Range Phenotype

Contribution of DNA Replication to the FAM111A-Mediated Simian Virus 40 Host Range Phenotype

Intermediates of adeno-associated virus type 2 assembly: identification of soluble complexes containing Rep and Cap proteins

The agnoprotein of polyomaviruses: A multifunctional auxiliary protein

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