small tumor antigen

File:Gaynor plospathogens 2007 WUvirusgenome.png, 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.{{Cite journal|last1=Gaynor|first1=Anne M.|last2=Nissen|first2=Michael D.|last3=Whiley|first3=David M.|last4=Mackay|first4=Ian M.|last5=Lambert|first5=Stephen B.|last6=Wu|first6=Guang|last7=Brennan|first7=Daniel C.|last8=Storch|first8=Gregory A.|last9=Sloots|first9=Theo P.|date=2007-05-04|title=Identification of a novel polyomavirus from patients with acute respiratory tract infections|journal=PLOS Pathogens|volume=3|issue=5|pages=e64|doi=10.1371/journal.ppat.0030064|issn=1553-7374|pmc=1864993|pmid=17480120 |doi-access=free }}]]

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).{{cite journal|last1=Moens|first1=U.|last2=Van Ghelue|first2=M.|last3=Johannessen|first3=M.|title=Oncogenic potentials of the human polyomavirus regulatory proteins|journal=Cellular and Molecular Life Sciences|date=5 May 2007|volume=64|issue=13|pages=1656–1678|doi=10.1007/s00018-007-7020-3|pmid=17483871|s2cid=31314244 |pmc=11136119}}{{cite journal|last1=Van Ghelue|first1=Marijke|last2=Khan|first2=Mahmud Tareq Hassan|last3=Ehlers|first3=Bernhard|last4=Moens|first4=Ugo|title=Genome analysis of the new human polyomaviruses|journal=Reviews in Medical Virology|date=November 2012|volume=22|issue=6|pages=354–377|doi=10.1002/rmv.1711|pmid=22461085|doi-access=free}} 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.{{cite journal|last1=Topalis|first1=D.|last2=Andrei|first2=G.|last3=Snoeck|first3=R.|title=The large tumor antigen: A "Swiss Army knife" protein possessing the functions required for the polyomavirus life cycle|journal=Antiviral Research|date=February 2013|volume=97|issue=2|pages=122–136|doi=10.1016/j.antiviral.2012.11.007|pmid=23201316}}

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.{{Cite journal|last1=Cheng|first1=Jingwei|last2=DeCaprio|first2=James A.|last3=Fluck|first3=Michele M.|last4=Schaffhausen|first4=Brian S.|title=Cellular transformation by Simian Virus 40 and Murine Polyoma Virus T antigens|journal=Seminars in Cancer Biology|volume=19|issue=4|pages=218–228|doi=10.1016/j.semcancer.2009.03.002|pmc=2694755|pmid=19505649|year=2009}} 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. These are believed to bind zinc in the SV40 STag and confer improved protein stability,{{cite journal|last1=Turk|first1=B|last2=Porras|first2=A|last3=Mumby|first3=MC|last4=Rundell|first4=K|title=Simian virus 40 small-t antigen binds two zinc ions.|journal=Journal of Virology|date=June 1993|volume=67|issue=6|pages=3671–3|pmid=8388518|pmc=237723|doi=10.1128/jvi.67.6.3671-3673.1993}}{{cite journal|last1=Goswami|first1=R|last2=Turk|first2=B|last3=Enderle|first3=K|last4=Howe|first4=A|last5=Rundell|first5=K|title=Effect of zinc ions on the biochemical behavior of simian virus 40 small-t antigen expressed in bacteria.|journal=Journal of Virology|date=March 1992|volume=66|issue=3|pages=1746–51|pmid=1310775|pmc=240925|doi=10.1128/jvi.66.3.1746-1751.1992}} but in Merkel cell polyomavirus STag, they have been reported to bind iron-sulfur clusters. 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.{{cite journal|last1=Buck|first1=Christopher B.|last2=Van Doorslaer|first2=Koenraad|last3=Peretti|first3=Alberto|last4=Geoghegan|first4=Eileen M.|last5=Tisza|first5=Michael J.|last6=An|first6=Ping|last7=Katz|first7=Joshua P.|last8=Pipas|first8=James M.|author8-link= James Pipas |last9=McBride|first9=Alison A.|last10=Camus|first10=Alvin C.|last11=McDermott|first11=Alexa J.|last12=Dill|first12=Jennifer A.|last13=Delwart|first13=Eric|last14=Ng|first14=Terry F. F.|last15=Farkas|first15=Kata|last16=Austin|first16=Charlotte|last17=Kraberger|first17=Simona|last18=Davison|first18=William|last19=Pastrana|first19=Diana V.|last20=Varsani|first20=Arvind|last21=Galloway|first21=Denise A.|title=The Ancient Evolutionary History of Polyomaviruses|journal=PLOS Pathogens|date=19 April 2016|volume=12|issue=4|pages=e1005574|doi=10.1371/journal.ppat.1005574|pmid=27093155|pmc=4836724 |doi-access=free }}

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. In Merkel cell polyomavirus, it appears to play a significant role in oncogenesis, a function performed primarily by LTag in other polyomaviruses. Where the tumor antigens' subcellular localization has been characterized, STag is usually located in the cytoplasm.

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.

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| image1 = 2pf4 pp2a stag.png

| caption1 = 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).{{Cite journal|last1=Cho|first1=Uhn Soo|last2=Morrone|first2=Seamus|last3=Sablina|first3=Anna A.|last4=Arroyo|first4=Jason D.|last5=Hahn|first5=William C.|last6=Xu|first6=Wenqing|date=2007-08-01|title=Structural basis of PP2A inhibition by small t antigen|journal=PLOS Biology|volume=5|issue=8|pages=e202|doi=10.1371/journal.pbio.0050202|issn=1545-7885|pmc=1945078|pmid=17608567 |doi-access=free }}

| image2 = 2iae pp2a trimer.png

| caption2 = The human protein phosphatase 2A (PP2A) heterotrimeric complex, shown with the regulatory subunit A (red), regulatory subunit B56 (green), and catalytic subunit (dark blue).{{Cite journal|last1=Cho|first1=Uhn Soo|last2=Xu|first2=Wenqing|date=2007-01-04|title=Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme|journal=Nature|volume=445|issue=7123|pages=53–57|doi=10.1038/nature05351|issn=1476-4687|pmid=17086192|bibcode=2007Natur.445...53C|s2cid=4408160 }} The overlap between the STag and B56 binding sites on the A subunit is clear.

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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.{{cite journal|last1=An|first1=Ping|last2=Sáenz Robles|first2=Maria Teresa|last3=Pipas|first3=James M.|author3-link= James Pipas |title=Large T Antigens of Polyomaviruses: Amazing Molecular Machines|journal=Annual Review of Microbiology|date=13 October 2012|volume=66|issue=1|pages=213–236|doi=10.1146/annurev-micro-092611-150154|pmid=22994493}}

STag contributes to this process through its interaction with protein phosphatase 2A (PP2A).{{cite journal|last1=Pallas|first1=David C.|last2=Shahrik|first2=Lilian K.|last3=Martin|first3=Bruce L.|last4=Jaspers|first4=Stephen|last5=Miller|first5=Thomas B.|last6=Brautigan|first6=David L.|last7=Roberts|first7=Thomas M.|title=Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A|journal=Cell|date=January 1990|volume=60|issue=1|pages=167–176|doi=10.1016/0092-8674(90)90726-U|pmid=2153055|s2cid=2007706 }} 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.{{cite journal|last1=Chen|first1=Y|last2=Xu|first2=Y|last3=Bao|first3=Q|last4=Xing|first4=Y|last5=Li|first5=Z|last6=Lin|first6=Z|last7=Stock|first7=JB|last8=Jeffrey|first8=PD|last9=Shi|first9=Y|title=Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40.|journal=Nature Structural & Molecular Biology|date=June 2007|volume=14|issue=6|pages=527–34|pmid=17529992|doi=10.1038/nsmb1254|s2cid=82822}}{{cite journal|last1=Sablina|first1=Anna A.|last2=Hahn|first2=William C.|title=SV40 small T antigen and PP2A phosphatase in cell transformation|journal=Cancer and Metastasis Reviews|date=23 January 2008|volume=27|issue=2|pages=137–146|doi=10.1007/s10555-008-9116-0|pmid=18214640|s2cid=7715684 }}

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.{{Cite journal|last1=Stakaitytė|first1=Gabrielė|last2=Wood|first2=Jennifer J.|last3=Knight|first3=Laura M.|last4=Abdul-Sada|first4=Hussein|last5=Adzahar|first5=Noor Suhana|last6=Nwogu|first6=Nnenna|last7=Macdonald|first7=Andrew|last8=Whitehouse|first8=Adrian|date=2014-06-27|title=Merkel Cell Polyomavirus: Molecular Insights into the Most Recently Discovered Human Tumour Virus|journal=Cancers|language=en|volume=6|issue=3|pages=1267–1297|doi=10.3390/cancers6031267|pmc=4190541|pmid=24978434|doi-access=free }} 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. In most polyomaviruses, STag's effect on transformation is mediated through its interaction with PP2A.

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.{{Cite journal|last1=Wendzicki|first1=Justin A.|last2=Moore|first2=Patrick S.|last3=Chang|first3=Yuan|date=2015-04-01|title=Large T and small T antigens of Merkel cell polyomavirus|journal=Current Opinion in Virology|volume=11|pages=38–43|doi=10.1016/j.coviro.2015.01.009|issn=1879-6265|pmc=4456251|pmid=25681708}} 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.{{cite journal|last1=Shuda|first1=Masahiro|last2=Kwun|first2=Hyun Jin|last3=Feng|first3=Huichen|last4=Chang|first4=Yuan|last5=Moore|first5=Patrick S.|title=Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator|journal=Journal of Clinical Investigation|date=1 September 2011|volume=121|issue=9|pages=3623–3634|doi=10.1172/JCI46323|pmid=21841310|pmc=3163959}} In vivo studies in rodent animal models suggest that MCPyV STag alone can be sufficient to drive transformation.{{Cite journal|last1=Verhaegen|first1=Monique E.|last2=Mangelberger|first2=Doris|last3=Harms|first3=Paul W.|last4=Vozheiko|first4=Tracy D.|last5=Weick|first5=Jack W.|last6=Wilbert|first6=Dawn M.|last7=Saunders|first7=Thomas L.|last8=Ermilov|first8=Alexandre N.|last9=Bichakjian|first9=Christopher K.|title=Merkel Cell Polyomavirus Small T Antigen Is Oncogenic in Transgenic Mice|journal=Journal of Investigative Dermatology|volume=135|issue=5|pages=1415–1424|doi=10.1038/jid.2014.446|pmc=4397111|pmid=25313532|year=2015}}

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{{Viral proteins}}

Category:Viral oncoproteins

Category:Polyomavirus proteins