scholarly journals Effect of the Large and Small T-Antigens of Human Polyomaviruses on Signaling Pathways

2019 ◽  
Vol 20 (16) ◽  
pp. 3914 ◽  
Author(s):  
Ugo Moens ◽  
Andrew Macdonald
Keyword(s):  
Host Cell ◽  
Signaling Pathways ◽  
Viral Infections ◽  
T Antigen ◽  
Progeny Virus ◽  
T Antigens ◽  
Dna Viruses ◽  
Intracellular Parasites ◽  
Host Signaling ◽  
Small T Antigen

Viruses are intracellular parasites that require a permissive host cell to express the viral genome and to produce new progeny virus particles. However, not all viral infections are productive and some viruses can induce carcinogenesis. Irrespective of the type of infection (productive or neoplastic), viruses hijack the host cell machinery to permit optimal viral replication or to transform the infected cell into a tumor cell. One mechanism viruses employ to reprogram the host cell is through interference with signaling pathways. Polyomaviruses are naked, double-stranded DNA viruses whose genome encodes the regulatory proteins large T-antigen and small t-antigen, and structural proteins that form the capsid. The large T-antigens and small t-antigens can interfere with several host signaling pathways. In this case, we review the interplay between the large T-antigens and small t-antigens with host signaling pathways and the biological consequences of these interactions.

scholarly journals Transactivation of Murine Cyclin A by Polyomavirus Large and Small T Antigens

2001 ◽  
Vol 75 (14) ◽  
pp. 6498-6507 ◽  
Author(s):  
Stefan Schüchner ◽  
Maria Nemethova ◽  
Aurelia Belisova ◽  
Britta Klucky ◽  
Wolfgang Holnthoner ◽  
...  
Keyword(s):  
Cyclin A ◽  
T Antigen ◽  
S Phase ◽  
Luciferase Reporter ◽  
Large T Antigen ◽  
3T3 Cells ◽  
T Antigens ◽  
J Domain ◽  
Swiss 3T3 ◽  
Small T Antigen

ABSTRACT Polyomavirus large and small T antigens cooperate in the induction of S phase in serum-deprived Swiss 3T3 cells. While the large T antigen is able to induce S phase-specific enzymes, we have recently shown that both T antigens contribute to the production of the cyclins E and A and that the small T antigen is essential for the induction of cyclin A-dependent cdk2 activity (S. Schüchner and E. Wintersberger, J. Virol. 73:9266–9273, 1999). Here we present our attempts to elucidate the mechanisms by which the large and the small T antigens transactivate the murine cyclin A gene. Using Swiss 3T3 cells carrying the T antigens and various mutants thereof under the hormone-inducible mouse mammary tumor virus promoter, as well as transient-cotransfection experiments with the T antigens and cyclin A promoter-luciferase reporter constructs, we found the following. The large T antigen activates the cyclin A promoter via two transcription factor binding sites, a cyclic AMP responsive element (CRE), and the major negative regulatory site called CDE-CHR. While an intact binding site for pocket proteins is required for the function of this T antigen at the CDE-CHR, its activity at the CRE is largely independent thereof. In contrast, an intact J domain and an intact zinc finger are required at both sites. The small T antigen also appears to have an influence on the cyclin A promoter through the CRE as well as the CDE-CHR. For this an interaction with protein phosphatase 2A is essential; mutation of the J domain does not totally eliminate but greatly reduces the transactivating ability.

ABC of viral infections in hematology: focus on herpesviruses

2019 ◽  
Vol 50 (3) ◽  
pp. 159-166 ◽  
Author(s):  
Jan Styczyński
Keyword(s):  
Host Cell ◽  
Influenza A ◽  
Hematopoietic Cell Transplantation ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Point Of View ◽  
Virus Infections ◽  
Dna Viruses ◽  
Form Of Life ◽  
Syncytial Virus

AbstractViruses are a form of life that possess genes but do not have a cellular structure. Viruses do not have their own metabolism, and they require a host cell to make new products; therefore, they cannot naturally reproduce outside a host cell. The objective of this paper is to present the basic practical clinical roles of viruses in patients with hematological diseases including malignancies and non-malignan- cies, as well as those undergoing hematopoietic cell transplantation (HCT), with the focus on herpesviruses causing latent infections in severely immunocompromised patients. From the hematologist point of view, viruses can play a major role in four conditions: causing infections; causing lymphoproliferations and/or malignancies; causing (pan)cytopenia; and used as vectors in treatment (e.g., gene therapy, CAR-T cells). Taking into account the role of viruses in hematology, infection is the most frequent condition. Among DNA viruses, the highest morbidity potential for human is expressed by Herpesviridiae (herpesviruses), Adenoviridae (adenovirus; ADV), Polyomavirus (BKV, JCV), and Bocavirus. RNA viruses can play a role in pathogenesis of different clinical conditions and diseases: lymphoproliferative disorders and malignancy, possibly causing NHL, AML, MDS, and others (HCV, HIV, and others); pancytopenia and aplastic anemia (HIV, HCV, Dengue virus); respiratory infections (community-acquired respiratory virus infections; CARV) caused by Orthomyxoviruses (e.g. influenza A/B), Paramyxoviruses (e.g. human parainfluenza virus PIV-1, -2, -3, and -4; respiratory syncytial virus RSV-A and -B), picornaviruses (e.g., human rhinovirus), coronaviruses (e.g., human coronavirus), Pneumoviridiae (e.g., human metapneumovirus), and potentially other viruses.

scholarly journals Novel Polyomaviruses in Mammals from Multiple Orders and Reassessment of Polyomavirus Evolution and Taxonomy

Viruses ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 930 ◽  
Author(s):  
Ehlers ◽  
Anoh ◽  
Ben Salem ◽  
Broll ◽  
Couacy-Hymann ◽  
...  
Keyword(s):  
Experimental Finding ◽  
Phylogenetic Analyses ◽  
T Antigen ◽  
Splice Sites ◽  
T Antigens ◽  
Edible Dormouse ◽  
The Family ◽  
Multiple Orders ◽  
Small T Antigen ◽  
Insight Into

As the phylogenetic organization of mammalian polyomaviruses is complex and currently incompletely resolved, we aimed at a deeper insight into their evolution by identifying polyomaviruses in host orders and families that have either rarely or not been studied. Sixteen unknown and two known polyomaviruses were identified in animals that belong to 5 orders, 16 genera, and 16 species. From 11 novel polyomaviruses, full genomes could be determined. Splice sites were predicted for large and small T antigen (LTAg, STAg) coding sequences (CDS) and examined experimentally in transfected cell culture. In addition, splice sites of seven published polyomaviruses were analyzed. Based on these data, LTAg and STAg annotations were corrected for 10/86 and 74/86 published polyomaviruses, respectively. For 25 polyomaviruses, a spliced middle T CDS was observed or predicted. Splice sites that likely indicate expression of additional, alternative T antigens, were experimentally detected for six polyomaviruses. In contrast to all other mammalian polyomaviruses, three closely related cetartiodactyl polyomaviruses display two introns within their LTAg CDS. In addition, the VP2 of Glis glis (edible dormouse) polyomavirus 1 was observed to be encoded by a spliced transcript, a unique experimental finding within the Polyomaviridae family. Co-phylogenetic analyses based on LTAg CDS revealed a measurable signal of codivergence when considering all mammalian polyomaviruses, most likely driven by relatively recent codivergence events. Lineage duplication was the only other process whose influence on polyomavirus evolution was unambiguous. Finally, our analyses suggest that an update of the taxonomy of the family is required, including the creation of novel genera of mammalian and non-mammalian polyomaviruses.

scholarly journals Malawi Polyomavirus Is a Prevalent Human Virus That Interacts with Known Tumor Suppressors

2014 ◽  
Vol 89 (1) ◽  
pp. 857-862 ◽  
Author(s):  
Christian Berrios ◽  
Joonil Jung ◽  
Blake Primi ◽  
Michael Wang ◽  
Chandrasekhar Pedamallu ◽  
...  
Keyword(s):  
Tumor Suppressors ◽  
Protein Phosphatase ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Human Polyomavirus ◽  
T Antigens ◽  
Human Virus ◽  
Phosphatase 2A ◽  
Small T Antigen

Malawi polyomavirus (MWPyV) is a recently identified human polyomavirus. Serology for MWPyV VP1 indicates that infection frequently occurs in childhood and reaches a prevalence of 75% in adults. The MWPyV small T antigen (ST) binds protein phosphatase 2A (PP2A), and the large T antigen (LT) binds pRb, p107, p130, and p53. However, the MWPyV LT was less stable than the simian virus 40 (SV40) LT and was unable to promote the growth of normal cells. This report confirms that MWPyV is a widespread human virus expressing T antigens with low transforming potential.

scholarly journals Effect on Polyomavirus T-Antigen Function of Mutations in a Conserved Leucine-Rich Segment of the DnaJ Domain

2001 ◽  
Vol 75 (5) ◽  
pp. 2253-2261 ◽  
Author(s):  
Hongyun Li ◽  
Karin Söderbärg ◽  
Hamid Houshmand ◽  
Zhi-Yong You ◽  
Göran Magnusson
Keyword(s):  
Amino Acid ◽  
Alpha Helix ◽  
Cellular Transformation ◽  
T Antigen ◽  
Phenotypic Change ◽  
Sequence Motif ◽  
Amino Acid Residues ◽  
Large T Antigen ◽  
T Antigens ◽  
Small T Antigen

ABSTRACT The N-terminal part of the mouse polyomavirus T antigens contains a highly conserved segment (-LLELLKL-), including amino acid residues 13 to 19. The sequence motif is predicted to form alpha helix I in the DnaJ domain of the T antigens. Four mutants with conservative substitutions of amino acid residues 13 and 14 were constructed. Of the four substitutions, L13M, L13I, L13V, and L14V, only L13V resulted in a phenotypic change. In transfected mouse cells, L13V large T antigen showed a more than 100-fold-reduced viral DNA synthesis. The viral replication could not be rescued by cotransfection of the cells with DNA expressing small t antigen or a large T antigen truncated at the C terminus that would compensate for a defect in host cell stimulation. In contrast to the effect on DNA replication, the L13V substitution in large T antigen did not prevent complex formation with Hsc70 and the Rb protein. Also, the activity of the protein in transactivation of transcription from the adenovirus E2 promoter was unimpaired, showing that the transcription factor E2F was released from pRb. The L13V substitution also caused a defect in small t antigen. However, this phenotypic change was due to protein instability. In contrast, middle T antigen with the L13V substitution remained stable and functional in cellular transformation. Together, the data show that the effect of the L13V substitution did not abrogate the Hsc70 interaction of the DnaJ domain. However, it is possible that the substitution of amino acid residue 13 affected specific DnaJ functions of large T antigen.

Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A

Cell ◽  
1990 ◽  
Vol 60 (1) ◽  
pp. 167-176 ◽  
Author(s):  
David C. Pallas ◽  
Lilian K. Shahrik ◽  
Bruce L. Martin ◽  
Stephen Jaspers ◽  
Thomas B. Miller ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
T Antigen ◽  
T Antigens ◽  
Phosphatase 2A ◽  
Small T Antigen ◽  
Sv40 Small T

scholarly journals Simian Virus 40 T Antigens and J Domains: Analysis of Hsp40 Cochaperone Functions in Escherichia coli

2003 ◽  
Vol 77 (19) ◽  
pp. 10706-10713 ◽  
Author(s):  
Pierre Genevaux ◽  
Florence Lang ◽  
Françoise Schwager ◽  
Jai V. Vartikar ◽  
Kathleen Rundell ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Loss Of Function ◽  
T Antigens ◽  
E Coli ◽  
J Domain ◽  
Small T Antigen

ABSTRACT The N-terminal exon of DNA tumor virus T antigens represents a J domain that can direct interaction with the host-encoded Hsp70 chaperones. We have taken advantage of rapid Hsp40 cochaperone assays with Escherichia coli to assess simian virus 40 (SV40)-encoded J-domain loss of function. We found a strong correlation between loss of cochaperone function in E. coli and defective SV40 growth, suggesting that the major role of the J domain in DNA tumor viruses is to provide cochaperone function. We also report the expression of native SV40 virus T antigens in E. coli. Our results show that small t antigen, but not large T antigen (LT) or LT truncation TN125 or TN136, can functionally replace under limited growth conditions DnaJ (Hsp40) function in vivo. In addition, purified small t antigen can efficiently stimulate E. coli DnaK's (Hsp70) ATPase in vitro, thus behaving like a bona fide cochaperone. Furthermore, small t amino acids 83 to 174, which are adjacent to the viral J domain, can replace the E. coli DnaJ J-domain glycine-phenylalanine-rich domain, immediately adjacent to the J-domain sequences, even in the absence of significant amino acid similarity to their DnaJ counterpart. Taken together, our studies demonstrate that functionally related Hsp40 proteins from mammalian viral systems can be rapidly studied in bacteria and exploited to probe the universally conserved Hsp70 chaperone machine mechanism.

scholarly journals Cell Biology of Viral Infections

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2431
Author(s):  
Pierre-Yves Lozach
Keyword(s):  
Host Cell ◽  
Cell Biology ◽  
Viral Infections ◽  
Life Forms ◽  
Original Research ◽  
Cellular Processes ◽  
Intracellular Parasites ◽  
Technological Developments ◽  
Life Threatening ◽  
Host Cell Interactions

Viruses exhibit an elegant simplicity, as they are so basic, but so frightening. Although only a few are life threatening, they have substantial implications for human health and the economy, as exemplified by the ongoing coronavirus pandemic. Viruses are rather small infectious agents found in all types of life forms, from animals and plants to prokaryotes and archaebacteria. They are obligate intracellular parasites, and as such, subvert many molecular and cellular processes of the host cell to ensure their own replication, amplification, and subsequent spread. This special issue addresses the cell biology of viral infections based on a collection of original research articles, communications, opinions, and reviews on various aspects of virus-host cell interactions. Together, these articles not only provide a glance into the latest research on the cell biology of viral infections, but also include novel technological developments.

scholarly journals The Simian Virus 40 Small-t and Large-T Antigens Jointly Regulate Cell Cycle Reentry in Human Fibroblasts

1999 ◽  
Vol 73 (4) ◽  
pp. 3102-3107 ◽  
Author(s):  
Analía Porrás ◽  
Stéphanie Gaillard ◽  
Kathleen Rundell
Keyword(s):  
Cell Cycle ◽  
Human Fibroblasts ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Large T Antigen ◽  
T Antigens ◽  
Cell Cycle Reentry ◽  
Small T Antigen ◽  
Hdf Cells

ABSTRACT Focus formation in human diploid fibroblasts (HDF cells) is known to require both the simian virus 40 (SV40) large-T and small-t antigens. Similarly, both SV40 proteins were required to stimulate confluent, density-arrested HDF cells to reenter the cell cycle. This study used defective recombinant adenoviruses to examine the roles of the individual SV40 proteins in altering specific steps in the cell cycle. Small-t antigen and, to a lesser extent, large-T antigen increased the level of the S phase cyclin cyclin A but without increasing the activity of associated cyclin kinases unless the two SV40 proteins were coexpressed. The absence of kinase activity reflected the presence in density-arrested cells of high levels of the cyclin-dependent kinase inhibitors p21WAF1 and p27KIP1. We report here that expression of SV40 large-T antigen reduced levels of p21WAF1, while expression of small-t antigen was required to decrease p27KIP1. The separate effects of large-T and small-t antigens on these two inhibitors may explain the joint requirement for the two proteins to drive cell cycle reentry of HDF cells and ultimately transform these cells.

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