Small tumor antigen

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The structure of part of the small tumor antigen from the SV40 polyomavirus, showing the J domain in yellow and the STag unique region in blue. Bound zinc ions are shown as pink spheres. Coordinating cysteine residues and residues in the domain interface are shown as sticks. 2pf4 stag.png
The structure of part of the small tumor antigen from the SV40 polyomavirus, showing the J domain in yellow and the STag unique region in blue. Bound zinc ions are shown as pink spheres. Coordinating cysteine residues and residues in the domain interface are shown as sticks.

The small tumor antigen (also called the small T-antigen and abbreviated STag or ST) is a protein encoded in the genomes of polyomaviruses, which are small double-stranded DNA viruses. STag is expressed early in the infectious cycle and is usually not essential for viral proliferation, though in most polyomaviruses it does improve replication efficiency. The STag protein is expressed from a gene that overlaps the large tumor antigen (LTag) such that the two proteins share an N-terminal DnaJ-like domain but have distinct C-terminal regions. STag is known to interact with host cell proteins, most notably protein phosphatase 2A (PP2A), and may activate the expression of cellular proteins associated with the cell cycle transition to S phase. In some polyomaviruses - such as the well-studied SV40, which natively infects monkeys - STag is unable to induce neoplastic transformation in the host cell on its own, but its presence may increase the transforming efficiency of LTag. [2] In other polyomaviruses, such as Merkel cell polyomavirus, which causes Merkel cell carcinoma in humans, STag appears to be important for replication and to be an oncoprotein in its own right. [3]

Contents

Structure and expression

Genome structure of WU virus, a typical human polyomavirus. The early genes are at left, comprising LTag (purple) and STag (blue); the late genes are at right, and the origin of replication is shown at the top of the figure. Gaynor plospathogens 2007 WUvirusgenome.png
Genome structure of WU virus, a typical human polyomavirus. The early genes are at left, comprising LTag (purple) and STag (blue); the late genes are at right, and the origin of replication is shown at the top of the figure.

The genes for both the small and the large tumor antigen are encoded in the "early region" of the polyomavirus genome, so named because this region of the genome is expressed early in the infectious process. (The "late region" contains genes encoding the viral capsid proteins.) The early region typically contains at least two genes and is transcribed as a single messenger RNA processed by alternative splicing. The LTag gene is usually encoded in two exons, of which the first overlaps with the gene for STag (and sometimes other tumor antigens as well, such as the murine polyomavirus middle tumor antigen). [2] [5] [6] Polyomavirus STag proteins are usually around 170-200 residues long and consist of two distinct regions as a result of this genetic encoding. STag and LTag share a common N-terminal domain called the J domain, which is around 80-90 residues long, has homology to DnaJ proteins, and functions as a molecular chaperone. [2] [7]

The C-terminal portion of the STag protein is distinct from LTag but shares an additional ~100 residues with middle tumor antigen in those viruses that express it, such as murine polyomavirus. [8] The C-terminal region of STag contains a protein phosphatase 2A binding region, followed in mammalian polyomaviruses by a metal ion binding region at the C-terminus with conserved cysteine-containing sequence motifs. [2] These are believed to bind zinc in the SV40 STag and confer improved protein stability, [2] [9] [10] but in Merkel cell polyomavirus STag, they have been reported to bind iron-sulfur clusters. [3] Among polyomaviruses that infect birds - classified in the genus Gammapolyomavirus - the conserved cysteines characterizing these metal-binding regions are not present and there is no detectable sequence homology between the avian and mammalian STag C-termini. [11]

Function

The exact functional role of STag varies among polyomaviruses. In SV40 and JC virus, STag is not required for viral proliferation, but does improve efficiency. In SV40, STag has a similar role in cellular transformation. [2] In Merkel cell polyomavirus, it appears to play a significant role in oncogenesis, a function performed primarily by LTag in other polyomaviruses. [3] Where the tumor antigens' subcellular localization has been characterized, STag is usually located in the cytoplasm. [8]

Viral replication

In most well-studied polyomaviruses, STag improves the efficiency of viral proliferation but is not essential. SV40 and murine polyomavirus STags appear to have a role in promoting host cell expression of genes under the control of certain types of promoters. This function is mediated by the J domain, presumably indirectly as STag has no DNA-binding ability of its own. Both STag and LTag interact through their J domains with Hsc70 to increase its ATPase activity. [2]

Effects on the cell cycle

2pf4 pp2a stag.png
The SV40 polyomavirus small tumor antigen (STag) J domain (yellow) and unique region (blue) in complex with the human protein phosphatase 2A (PP2A) A subunit (red). [1]
2iae pp2a trimer.png
The human protein phosphatase 2A (PP2A) heterotrimeric complex, shown with the regulatory subunit A (red), regulatory subunit B56 (green), and catalytic subunit (dark blue). [12] The overlap between the STag and B56 binding sites on the A subunit is clear.

Because polyomavirus genome replication relies on the DNA replication machinery of the host cell, the cell must be in S phase (the part of the cell cycle in which the host cell's genome is normally replicated) in order to provide the necessary molecular machinery for viral DNA replication. Viral proteins therefore promote dysregulation of the cell cycle and entry into S phase. This function is usually primarily provided by LTag through its interactions with retinoblastoma protein and p53. [7] [13]

STag contributes to this process through its interaction with protein phosphatase 2A (PP2A). [14] The active form of PP2A consists of a heterotrimer assembly of three subunits. X-ray crystallography of the STag-PP2A protein complex demonstrates that STag replaces one subunit in the complex, thereby inactivating it. [2] [1] [15] [16]

Cellular transformation

Some, but not all, polyomaviruses are oncoviruses capable of inducing neoplastic transformation in some cells. In oncogenic polyomaviruses, the tumor antigens are responsible for the transformation activity, although the exact molecular mechanisms vary from one virus to another. [13] [7] [17] STag is usually not capable of inducing these effects on its own, but increases efficiency of transformation or is sometimes a required component in addition to LTag. [2] In most polyomaviruses, STag's effect on transformation is mediated through its interaction with PP2A. [16]

Distinct functions in Merkel cell polyomavirus

Merkel cell polyomavirus (MCPyV) is a virus causally associated with a rare and aggressive human skin cancer called Merkel cell carcinoma. MCPyV genetic material is often found integrated into the tumor cell genome, usually with mutations in the tumor antigen genes that abrogate the helicase activity of LTag, which is required for normal viral replication. [3] [18] In MCPyV, STag, rather than LTag, is the primary oncoprotein, is found in Merkel cell carcinomas more often than LTag, is required for tumor growth, and has additional pro-transformation effects independent of its PP2A-binding activity. MCPyV STag is believed to induce dysregulation of cap-dependent translation by promoting phosphorylation of eukaryotic translation initiation factor 4E-BP1. [19] In vivo studies in rodent animal models suggest that MCPyV STag alone can be sufficient to drive transformation. [20]

Related Research Articles

<i>Polyomaviridae</i> Family of viruses

Polyomaviridae is a family of viruses whose natural hosts are primarily mammals and birds. As of 2020, there are six recognized genera and 117 species, five of which are unassigned to a genus. 14 species are known to infect humans, while others, such as Simian Virus 40, have been identified in humans to a lesser extent. Most of these viruses are very common and typically asymptomatic in most human populations studied. BK virus is associated with nephropathy in renal transplant and non-renal solid organ transplant patients, JC virus with progressive multifocal leukoencephalopathy, and Merkel cell virus with Merkel cell cancer.

SV40 is an abbreviation for simian vacuolating virus 40 or simian virus 40, a polyomavirus that is found in both monkeys and humans. Like other polyomaviruses, SV40 is a DNA virus that sometimes causes tumors in animals, but most often persists as a latent infection. SV40 has been widely studied as a model eukaryotic virus, leading to many early discoveries in eukaryotic DNA replication and transcription.

<span class="mw-page-title-main">Oncovirus</span> Viruses that can cause cancer

An oncovirus or oncogenic virus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, when the term "oncornaviruses" was used to denote their RNA virus origin. With the letters "RNA" removed, it now refers to any virus with a DNA or RNA genome causing cancer and is synonymous with "tumor virus" or "cancer virus". The vast majority of human and animal viruses do not cause cancer, probably because of longstanding co-evolution between the virus and its host. Oncoviruses have been important not only in epidemiology, but also in investigations of cell cycle control mechanisms such as the retinoblastoma protein.

<span class="mw-page-title-main">SV40 large T antigen</span> Proto-oncogene derived from polyomavirus SV40

SV40 large T antigen is a hexamer protein that is a dominant-acting oncoprotein derived from the polyomavirus SV40. TAg is capable of inducing malignant transformation of a variety of cell types. The transforming activity of TAg is due in large part to its perturbation of the retinoblastoma (pRb) and p53 tumor suppressor proteins. In addition, TAg binds to several other cellular factors, including the transcriptional co-activators p300 and CBP, which may contribute to its transformation function. Similar proteins from related viruses are known as large tumor antigen in general.

Merkel cell polyomavirus was first described in January 2008 in Pittsburgh, Pennsylvania. It was the first example of a human viral pathogen discovered using unbiased metagenomic next-generation sequencing with a technique called digital transcriptome subtraction. MCV is one of seven currently known human oncoviruses. It is suspected to cause the majority of cases of Merkel cell carcinoma, a rare but aggressive form of skin cancer. Approximately 80% of Merkel cell carcinoma (MCC) tumors have been found to be infected with MCV. MCV appears to be a common—if not universal—infection of older children and adults. It is found in respiratory secretions, suggesting that it might be transmitted via a respiratory route. However, it has also been found elsewhere, such as in shedded healthy skin and gastrointestinal tract tissues, thus its precise mode of transmission remains unknown. In addition, recent studies suggest that this virus may latently infect the human sera and peripheral blood mononuclear cells.

Trichodysplasia spinulosa polyomavirus is a member virus of Human polyomavirus 8 that infects human hosts. First discovered in 2010, TSPyV is associated with Trichodysplasia spinulosa, a rare skin disease only seen in immunocompromised patients. The virus causes hyperproliferation and enlargement of hair follicles by modulating PP2A protein phosphatase signaling pathways. TSPyV was the eighth human polyomavirus to be discovered, and one of four associated with human disease, out of 13 human polyomaviruses known as of the 2015 update to polyomavirus taxonomy released by the International Committee on Taxonomy of Viruses.

<span class="mw-page-title-main">Murine polyomavirus</span> Species of virus

Murine polyomavirus is an unenveloped double-stranded DNA virus of the polyomavirus family. The first member of the family discovered, it was originally identified by accident in the 1950s. A component of mouse leukemia extract capable of causing tumors, particularly in the parotid gland, in newborn mice was reported by Ludwik Gross in 1953 and identified as a virus by Sarah Stewart and Bernice Eddy at the National Cancer Institute, after whom it was once called "SE polyoma". Stewart and Eddy would go on to study related polyomaviruses such as SV40 that infect primates, including humans. These discoveries were widely reported at the time and formed the early stages of understanding of oncoviruses.

<span class="mw-page-title-main">Major capsid protein VP1</span>

Major capsid protein VP1 is a viral protein that is the main component of the polyomavirus capsid. VP1 monomers are generally around 350 amino acids long and are capable of self-assembly into an icosahedral structure consisting of 360 VP1 molecules organized into 72 pentamers. VP1 molecules possess a surface binding site that interacts with sialic acids attached to glycans, including some gangliosides, on the surfaces of cells to initiate the process of viral infection. The VP1 protein, along with capsid components VP2 and VP3, is expressed from the "late region" of the circular viral genome.

Hamster polyomavirus is an unenveloped double-stranded DNA virus of the polyomavirus family whose natural host is the hamster. It was originally described in 1967 by Arnold Graffi as a cause of epithelioma in Syrian hamsters.

WU polyomavirus is a virus of the family Polyomaviridae. It was discovered in 2007 in samples of human respiratory secretions, originally from a child patient in Australia who presented with clinical signs of pneumonia and in whom other common respiratory viruses were not detected. Follow-up studies identified the presence of WU virus in respiratory secretion samples from patients in Australia and the United States, suggesting that, like other human polyomaviruses, WU virus is widely distributed.

KI polyomavirus is a virus of the family Polyomaviridae. It was discovered in 2007 in stored samples of human respiratory secretions collected by the Karolinska Institute, after which the virus is named.

<span class="mw-page-title-main">Agnoprotein</span> Viral protein found in some polyomaviruses

Agnoprotein is a protein expressed by some members of the polyomavirus family from a gene called the agnogene. Polyomaviruses in which it occurs include two human polyomaviruses associated with disease, BK virus and JC virus, as well as the simian polyomavirus SV40.

Human polyomavirus 7 (HPyV7) is a virus of the polyomavirus family that infects human hosts. It was discovered in 2010 and is a common component of the skin flora in healthy adults. There is limited evidence from case reports linking the virus to a skin rash occurring in immunocompromised organ transplant recipients.

Human polyomavirus 6 (HPyV6) is a virus of the polyomavirus family that infects human hosts. It was discovered in 2010 and is a component of the skin flora in healthy adults.

MW polyomavirus is a virus of the polyomavirus family that infects human hosts. It was discovered in 2012 and reported independently by several research groups. It has been identified mostly in stool samples from children and has been detected in a variety of geographic locations.

STL polyomavirus is a virus of the polyomavirus family that infects human hosts. It was first reported in 2013 and is most closely related to MW polyomavirus. It has been identified mostly in stool samples from children and has been detected in a variety of geographic locations.

New Jersey polyomavirus is a virus of the polyomavirus family that infects human hosts. It was first identified in 2014 in a pancreatic transplant patient in New Jersey. It is the 13th and most recent human polyomavirus to be described.

<span class="mw-page-title-main">Large tumor antigen</span>

The large tumor antigen is a protein encoded in the genomes of polyomaviruses, which are small double-stranded DNA viruses. LTag is expressed early in the infectious cycle and is essential for viral proliferation. Containing four well-conserved protein domains as well as several intrinsically disordered regions, LTag is a fairly large multifunctional protein; in most polyomaviruses, it ranges from around 600-800 amino acids in length. LTag has two primary functions, both related to replication of the viral genome: it unwinds the virus's DNA to prepare it for replication, and it interacts with proteins in the host cell to dysregulate the cell cycle so that the host's DNA replication machinery can be used to replicate the virus's genome. Some polyomavirus LTag proteins - most notably the well-studied SV40 large tumor antigen from the SV40 virus - are oncoproteins that can induce neoplastic transformation in the host cell.

The middle tumor antigen is a protein encoded in the genomes of some polyomaviruses, which are small double-stranded DNA viruses. MTag is expressed early in the infectious cycle along with two other related proteins, the small tumor antigen and large tumor antigen. MTag occurs only in a few known polyomaviruses, while STag and LTag are universal - it was first identified in mouse polyomavirus (MPyV), the first polyomavirus discovered, and also occurs in hamster polyomavirus. In MPyV, MTag is an efficient oncoprotein that can be sufficient to induce neoplastic transformation in some cells.

Minor capsid protein VP2 and minor capsid protein VP3 are viral proteins that are components of the polyomavirus capsid. Polyomavirus capsids are composed of three proteins; the major component is major capsid protein VP1, which self-assembles into pentamers that in turn self-assemble into enclosed icosahedral structures. The minor components are VP2 and VP3, which bind in the interior of the capsid.

References

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  3. 1 2 3 4 Tsang, Sabrina H.; Wang, Ranran; Nakamaru-Ogiso, Eiko; Knight, Simon A. B.; Buck, Christopher B.; You, Jianxin; Banks, L. (1 February 2016). "The Oncogenic Small Tumor Antigen of Merkel Cell Polyomavirus Is an Iron-Sulfur Cluster Protein That Enhances Viral DNA Replication". Journal of Virology. 90 (3): 1544–1556. doi:10.1128/JVI.02121-15. PMC   4719616 . PMID   26608318.
  4. ↑ Gaynor, Anne M.; Nissen, Michael D.; Whiley, David M.; Mackay, Ian M.; Lambert, Stephen B.; Wu, Guang; Brennan, Daniel C.; Storch, Gregory A.; Sloots, Theo P. (2007-05-04). "Identification of a novel polyomavirus from patients with acute respiratory tract infections". PLOS Pathogens. 3 (5): e64. doi: 10.1371/journal.ppat.0030064 . ISSN   1553-7374. PMC   1864993 . PMID   17480120.
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  15. ↑ Chen, Y; Xu, Y; Bao, Q; Xing, Y; Li, Z; Lin, Z; Stock, JB; Jeffrey, PD; Shi, Y (June 2007). "Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40". Nature Structural & Molecular Biology. 14 (6): 527–34. doi:10.1038/nsmb1254. PMID   17529992. S2CID   82822.
  16. 1 2 Sablina, Anna A.; Hahn, William C. (23 January 2008). "SV40 small T antigen and PP2A phosphatase in cell transformation". Cancer and Metastasis Reviews. 27 (2): 137–146. doi:10.1007/s10555-008-9116-0. PMID   18214640. S2CID   7715684.
  17. ↑ Stakaitytė, Gabrielė; Wood, Jennifer J.; Knight, Laura M.; Abdul-Sada, Hussein; Adzahar, Noor Suhana; Nwogu, Nnenna; Macdonald, Andrew; Whitehouse, Adrian (2014-06-27). "Merkel Cell Polyomavirus: Molecular Insights into the Most Recently Discovered Human Tumour Virus". Cancers. 6 (3): 1267–1297. doi: 10.3390/cancers6031267 . PMC   4190541 . PMID   24978434.
  18. ↑ Wendzicki, Justin A.; Moore, Patrick S.; Chang, Yuan (2015-04-01). "Large T and small T antigens of Merkel cell polyomavirus". Current Opinion in Virology. 11: 38–43. doi:10.1016/j.coviro.2015.01.009. ISSN   1879-6265. PMC   4456251 . PMID   25681708.
  19. ↑ Shuda, Masahiro; Kwun, Hyun Jin; Feng, Huichen; Chang, Yuan; Moore, Patrick S. (1 September 2011). "Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator". Journal of Clinical Investigation. 121 (9): 3623–3634. doi:10.1172/JCI46323. PMC   3163959 . PMID   21841310.
  20. ↑ Verhaegen, Monique E.; Mangelberger, Doris; Harms, Paul W.; Vozheiko, Tracy D.; Weick, Jack W.; Wilbert, Dawn M.; Saunders, Thomas L.; Ermilov, Alexandre N.; Bichakjian, Christopher K. (2015). "Merkel Cell Polyomavirus Small T Antigen Is Oncogenic in Transgenic Mice". Journal of Investigative Dermatology. 135 (5): 1415–1424. doi:10.1038/jid.2014.446. PMC   4397111 . PMID   25313532.
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