Murine polyomavirus: Difference between revisions

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==Structure==
==Structure==
[[File:Polyomavirus_(14550144862).jpg|thumb|A [[3D printed]] model of a polyomavirus capsid.]]
[[File:Polyomavirus_(14550144862).jpg|thumb|A [[3D printed]] model of a polyomavirus capsid.]]
Like other members of the polyomavirus family, MPyV has a closed, circular [[double-stranded]] [[DNA]] [[genome]] of around 5 [[kilo-base pair]]s and an unenveloped [[icosahedral]] ([[Triangulation number|T]]=7) [[viral capsid]] around 45 [[nanometer]]s in diameter.<ref name=ramqvist_scb /><ref name=ramqvist_acr>{{cite journal|last1=Ramqvist|first1=T|last2=Dalianis|first2=T|title=Lessons from immune responses and vaccines against murine polyomavirus infection and polyomavirus-induced tumours potentially useful for studies on human polyomaviruses.|journal=Anticancer research|date=February 2010|volume=30|issue=2|pages=279-84|pmid=20332429}}</ref> The capsid contains three [[viral protein|protein]]s; [[Polyomavirus capsid protein (VP1)|capsid protein VP1]] is the primary component and self-assembles into a 360-unit outer capsid layer composed of 72 pentamers. The other two components, VP2 and VP3, have high [[sequence similarity]] to each other, with VP3 truncated at the [[N-terminus]] relative to VP2. VP2 and VP3 assemble inside the capsid in contact with VP1.<ref name=ramqvist_scb /><ref name=ramqvist_acr />
Like other members of the polyomavirus family, MPyV has an unenveloped [[icosahedral]] ([[Triangulation number|T]]=7) [[viral capsid]] around 45 [[nanometer]]s in diameter.<ref name=ramqvist_scb /><ref name=ramqvist_acr>{{cite journal|last1=Ramqvist|first1=T|last2=Dalianis|first2=T|title=Lessons from immune responses and vaccines against murine polyomavirus infection and polyomavirus-induced tumours potentially useful for studies on human polyomaviruses.|journal=Anticancer research|date=February 2010|volume=30|issue=2|pages=279-84|pmid=20332429}}</ref> The capsid contains three [[viral protein|protein]]s; [[Polyomavirus capsid protein (VP1)|capsid protein VP1]] is the primary component and self-assembles into a 360-unit outer capsid layer composed of 72 pentamers. The other two components, VP2 and VP3, have high [[sequence similarity]] to each other, with VP3 truncated at the [[N-terminus]] relative to VP2. VP2 and VP3 assemble inside the capsid in contact with VP1.<ref name=ramqvist_scb /><ref name=ramqvist_acr />
[[File:Mpyv_colorbychain.png|thumb|A capsid structure colored to illustrate the assembly of the icosahedral architecture from VP1 pentamers. Each symmetrically related VP1 monomer is shown in a different color. From {{PDB|1SIE}}.]]
[[File:Mpyv_colorbychain.png|thumb|A capsid structure colored to illustrate the assembly of the icosahedral architecture from VP1 pentamers. Each symmetrically related VP1 monomer is shown in a different color. From {{PDB|1SIE}}.]]

==Genome==
MPyV has a closed, circular [[double-stranded]] [[DNA]] [[genome]] of around 5 [[kilo-base pair]]s. It contains two transcriptional units located on opposite strands, called the "early region" and "late region" for the stage in the viral life cycle in which they are [[gene expression|expressed]]; each region produces a [[pre-mRNA|pre-messenger RNA]] molecule from which six [[gene]]s are expressed through [[alternative splicing]]. The three genes in the early region express the large, middle, and small [[tumor antigen]]s (LT, MT, ST) and are sufficient for inducing tumors. The three genes in the late region express the three capsid proteins VP1, VP2, and VP3. Between the early and late regions is a region of [[noncoding DNA]] containing the [[origin of replication]] and [[promoter (genetics)|promoter]] and [[enhancer (genetics)|enhancer]] elements.<ref>{{cite book|last1=Lawrence|first1=editor-in-chief, Sir John Kendrew ; executive editor, Eleanor|title=The encyclopedia of molecular biology|date=1994|publisher=Blackwell Science|location=Oxford|isbn=9781444313840}}</ref>{{rp|786-7}} Expression of a [[microRNA]] from a region overlapping one of the LT [[exon]]s has also been identified and is thought to be involved in downregulating expression of the tumor antigens.<ref>{{cite journal|last1=Lagatie|first1=Ole|last2=Tritsmans|first2=Luc|last3=Stuyver|first3=Lieven J|title=The miRNA world of polyomaviruses|journal=Virology Journal|date=2013|volume=10|issue=1|pages=268|doi=10.1186/1743-422X-10-268|pmid=23984639}}</ref>


==Cellular entry==
==Cellular entry==

Revision as of 05:04, 12 July 2015

Murine polyomavirus
A rendering of an icosahedral viral capsid comprising 72 pentamers of VP1, colored such that areas of the surface closer to the interior center appear blue and areas further away appear red.
The capsid protein VP1 assembled into an icosahedral capsid structure comprising 72 pentamers, colored by distance from the interior center. From PDB: 1SIE​.[1]
Virus classification
Group:
Group I (dsDNA)
Family:
Polyomaviridae
Genus:
Polyomavirus
Species:
Murine polyomavirus

Murine polyomavirus (also known as mouse polyomavirus or Polyomavirus muris, and in older literature SE polyoma or parotid tumor virus; abbreviated MPyV) is an unenveloped double-stranded DNA virus of the polyomavirus family. It was originally identified by accident in the 1950s;[2] a component of mouse leukemia extract capable of causing tumors, particularly in the parotid gland, in newborn mice was reported by Ludwig Gross in 1953[3] and identified as a virus by Sarah Stewart and Bernice Eddy at the National Cancer Institute, after whom it was once called "SE polyoma".[4][5][6] 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.[7][8]

Pathology

MPyV is primarily spread among mice via the intranasal route and is shed in urine. Genetic susceptibility to MPyV infection among mice varies significantly, and not all MPyV strains are oncogenic.[6] In general, only newborns and immunosuppressed mice (usually transgenic) develop tumors upon infection; although originally observed as a cause of parotid gland tumors, the virus may induce solid tumors in a wide variety of tissue types of both epithelial and mesenchymal origin.[9]: 107–9  Under natural conditions the virus does not cause tumors; maternal antibodies have been shown to be critical in protecting neonates.[9][10] MPyV has been described as rare in modern laboratory mouse research colonies.[6]

MPyV is also capable of infecting and causing tumors in other rodent species, including guinea pigs, hamsters, and rats, though the diversity of tissue types giving rise to tumors is reduced in these species.[9]: 107–9 

Structure

A 3D printed model of a polyomavirus capsid.

Like other members of the polyomavirus family, MPyV has an unenveloped icosahedral (T=7) viral capsid around 45 nanometers in diameter.[10][11] The capsid contains three proteins; capsid protein VP1 is the primary component and self-assembles into a 360-unit outer capsid layer composed of 72 pentamers. The other two components, VP2 and VP3, have high sequence similarity to each other, with VP3 truncated at the N-terminus relative to VP2. VP2 and VP3 assemble inside the capsid in contact with VP1.[10][11]

A capsid structure colored to illustrate the assembly of the icosahedral architecture from VP1 pentamers. Each symmetrically related VP1 monomer is shown in a different color. From PDB: 1SIE​.

Genome

MPyV has a closed, circular double-stranded DNA genome of around 5 kilo-base pairs. It contains two transcriptional units located on opposite strands, called the "early region" and "late region" for the stage in the viral life cycle in which they are expressed; each region produces a pre-messenger RNA molecule from which six genes are expressed through alternative splicing. The three genes in the early region express the large, middle, and small tumor antigens (LT, MT, ST) and are sufficient for inducing tumors. The three genes in the late region express the three capsid proteins VP1, VP2, and VP3. Between the early and late regions is a region of noncoding DNA containing the origin of replication and promoter and enhancer elements.[12]: 786–7  Expression of a microRNA from a region overlapping one of the LT exons has also been identified and is thought to be involved in downregulating expression of the tumor antigens.[13]

Cellular entry

A series of thawed cryosections of cells infected with MPyV illustrating the process of viral internalization. "pm" notation indicates the position of the plasma membrane.[14]

Viruses lacking a viral envelope often have complex mechanisms for entry into the host cell. MPyV capsid protein VP1 binds to sialic acids of gangliosides GD1a and GT1b on the cell surface.[1][15] The functions of VP2 and VP3 are less well understood, but at least VP2 has been reported to be exposed upon endocytosis of the viral particle and may be involved in releasing the virus from the endoplasmic reticulum.[16][17] MPyV has been reported to enter cells through both a caveolae-dependent endocytosis mechanism and by an independent mechanism through uncoated vesicles.[17][18]

Unlike many viruses that enter the cell through endocytosis, polyomaviruses penetrate the cell membrane and enter the cytosol from the late endoplasmic reticulum rather than from endosomes, although onformational changes in response to low pH in endolysosomes have been hypothesized as critical steps in the process.[19] MPyV membrane exit is believed to depend on the presence of specific host proteins located in the late ER; for example, the host protein ERp29, a member of the protein disulfide isomerase family, has been shown to disrupt the conformation of VP1.[20] It is not known whether entry into the cytosol is obligatory for MPyV infection or whether the particle could enter the cell nucleus directly from the ER. Even a single viral particle entering the nucleus can be sufficient for infection.[17]

Tumorigenesis

MPyV contains three proteins extensively studied for their ability to induce neoplastic transformation (that is, carcinogenesis), which have been designated large, middle, and small tumor antigen (LT, MT, ST). PMyV and its close relative hamster polyomavirus are the only known polyomaviruses to contain middle tumor antigen, by far the most efficient of the three at inducing carcinogenesis, to the point that expression of MT from a transgene or introduction in cell culture can be sufficient to induce transformation. Studies using MT have been critical in understanding host-cell oncogenes and their effects on carcinogenesis, particularly in the study of the Src family of tyrosine kinases.[21]

References

  1. ^ a b Stehle, T; Harrison, SC (15 February 1996). "Crystal structures of murine polyomavirus in complex with straight-chain and branched-chain sialyloligosaccharide receptor fragments". Structure (London, England : 1993). 4 (2): 183–94. PMID 8805524.
  2. ^ Gross, L (November 1976). "The fortuitous isolation and identification of the polyoma virus". Cancer research. 36 (11 Pt 1): 4195–6. PMID 184928.
  3. ^ Gross, L. (1953). "A Filterable Agent, Recovered from Ak Leukemic Extracts, Causing Salivary Gland Carcinomas in C3H Mice". Experimental Biology and Medicine. 83 (2): 414–21. doi:10.3181/00379727-83-20376. PMID 13064287.
  4. ^ STEWART, SE; EDDY, BE; BORGESE, N (June 1958). "Neoplasms in mice inoculated with a tumor agent carried in tissue culture". Journal of the National Cancer Institute. 20 (6): 1223–43. PMID 13549981.
  5. ^ Eddy, Bernice E.; Stewart, Sarah E. (November 1959). "Characteristics of the SE Polyoma Virus". American Journal of Public Health and the Nations Health. 49 (11): 1486–1492. doi:10.2105/AJPH.49.11.1486.
  6. ^ a b c Percy, Dean H.; Barthold, Stephen W. (2013). "Polyoma Virus Infection". Pathology of Laboratory Rodents and Rabbits (3rd ed.). John Wiley & Sons. ISBN 1118704630.
  7. ^ Harris, R.J.C. (7 July 1960). "Cancer-inducing Viruses". The New Scientist. 8 (190): 21–3.
  8. ^ Morgan, Gregory J. (December 2014). "Ludwik Gross, Sarah Stewart, and the 1950s discoveries of Gross murine leukemia virus and polyoma virus". Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences. 48: 200–209. doi:10.1016/j.shpsc.2014.07.013.
  9. ^ a b c al.], edited by James G. Fox ... [et (2006). The Mouse in Biomedical Research, Volume 2 Diseases (2nd ed. ed.). Burlington: Elsevier. ISBN 9780080467719. {{cite book}}: |edition= has extra text (help); |first1= has generic name (help)
  10. ^ a b c Ramqvist, T; Dalianis, T (August 2009). "Murine polyomavirus tumour specific transplantation antigens and viral persistence in relation to the immune response, and tumour development". Seminars in cancer biology. 19 (4): 236–43. PMID 19505651.
  11. ^ a b Ramqvist, T; Dalianis, T (February 2010). "Lessons from immune responses and vaccines against murine polyomavirus infection and polyomavirus-induced tumours potentially useful for studies on human polyomaviruses". Anticancer research. 30 (2): 279–84. PMID 20332429.
  12. ^ Lawrence, editor-in-chief, Sir John Kendrew ; executive editor, Eleanor (1994). The encyclopedia of molecular biology. Oxford: Blackwell Science. ISBN 9781444313840. {{cite book}}: |first1= has generic name (help)CS1 maint: multiple names: authors list (link)
  13. ^ Lagatie, Ole; Tritsmans, Luc; Stuyver, Lieven J (2013). "The miRNA world of polyomaviruses". Virology Journal. 10 (1): 268. doi:10.1186/1743-422X-10-268. PMID 23984639.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  14. ^ Zila, V; Difato, F; Klimova, L; Huerfano, S; Forstova, J (2014). "Involvement of microtubular network and its motors in productive endocytic trafficking of mouse polyomavirus". PloS one. 9 (5): e96922. PMID 24810588.
  15. ^ Tsai, B; Gilbert, JM; Stehle, T; Lencer, W; Benjamin, TL; Rapoport, TA (1 September 2003). "Gangliosides are receptors for murine polyoma virus and SV40". The EMBO journal. 22 (17): 4346–55. PMID 12941687.
  16. ^ Burkert, O; Kreßner, S; Sinn, L; Giese, S; Simon, C; Lilie, H (July 2014). "Biophysical characterization of polyomavirus minor capsid proteins". Biological chemistry. 395 (7–8): 871–80. PMID 24713574.
  17. ^ a b c Tsai, B; Qian, M (2010). "Cellular entry of polyomaviruses". Current topics in microbiology and immunology. 343: 177–94. PMID 20373089.
  18. ^ Gilbert, JM; Benjamin, TL (September 2000). "Early steps of polyomavirus entry into cells". Journal of virology. 74 (18): 8582–8. PMID 10954560.
  19. ^ Qian, M; Cai, D; Verhey, KJ; Tsai, B (June 2009). "A lipid receptor sorts polyomavirus from the endolysosome to the endoplasmic reticulum to cause infection". PLoS pathogens. 5 (6): e1000465. PMID 19503604.
  20. ^ Magnuson, B; Rainey, EK; Benjamin, T; Baryshev, M; Mkrtchian, S; Tsai, B (28 October 2005). "ERp29 triggers a conformational change in polyomavirus to stimulate membrane binding". Molecular cell. 20 (2): 289–300. PMID 16246730.
  21. ^ Fluck, MM; Schaffhausen, BS (September 2009). "Lessons in signaling and tumorigenesis from polyomavirus middle T antigen". Microbiology and molecular biology reviews : MMBR. 73 (3): 542–63, Table of Contents. PMID 19721090.

Media related to MPyV-infected nuclei and MPyV virus factories at Wikimedia Commons

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