Agnoprotein

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Agnoprotein
2mj2.png
Nuclear magnetic resonance structure of the helix-containing hydrophobic region of the JC virus agnoprotein. [1]
Identifiers
SymbolPolyoma_agno
Pfam PF01736
InterPro IPR002643
OPM superfamily 405
OPM protein 2mj2
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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. [2]

Contents

Sequence and structure

Agnoprotein is typically quite short: examples from BK virus, JC virus, and SV40 are 62, 71, and 66 amino acid residues long, respectively. Among other known polyomavirus genomes with a predicted agnogene, the length of the resulting predicted protein varies considerably, from as short as 30 to as long as 154 residues. [3] It contains a highly hydrophobic central amino acid sequence, a "bipartite" nuclear localization sequence at the N-terminus, and highly basic amino acids at both termini. Comparison of the sequences of different viral agnoproteins suggests sequence conservation toward the N-terminus with greater variability toward the C-terminus. Formation of amphipathic alpha helices under laboratory conditions has been demonstrated for part of the sequence believed to have a role in mediating dimerization and oligomerization of the protein. [1] [2] [4] The BK, JC, and SV40 agnoproteins have all been experimentally demonstrated to be phosphorylated in vivo, which appears to improve both protein stability and viral propagation, but no other post-translational modifications have been detected. [2] [3]

Expression

A map of the genome of JC virus, indicating the position of the agnogene (yellow) in the late region relative to the other coding genes and to the non-coding control region (NCCR). Wharton plosone 2016.png
A map of the genome of JC virus, indicating the position of the agnogene (yellow) in the late region relative to the other coding genes and to the non-coding control region (NCCR).

Agnoprotein is expressed from a region of the circular viral genome called the agnogene, an open reading frame contained in a region of the polyomavirus genome that codes for the viral capsid proteins and is known as the "late region" because it is expressed late in the cycle of viral infection and replication. [2] The agnogene and its protein product received their name (from the Greek agnosis , "without knowledge" [3] ) because the presence of the open reading frame and corresponding RNA was detected before the existence of the protein product was confirmed. [6]

Cellular localization

Agnoprotein is consistently detected in the cytoplasm of infected cells, with particularly high concentrations in the perinuclear space. It is also detectable in the cell nucleus; in the case of JC virus, nuclear-localized agnoprotein comprises 15–20% of the total agnoprotein expressed. [2]

Function

Agnoprotein is a regulatory protein required for efficient proliferation of the viruses in which it is present, although many polyomaviruses do not have the gene. [4] Its functions are poorly characterized even in well-studied viruses. Null mutant viruses without agnoprotein are generally either incapable of proliferation or are vastly impaired; some such mutants can produce virions, but they may be deficient in exiting the host cell or lack appropriately packaged genetic material. [7] [8] Agnoprotein null mutants can successfully proliferate if agnoprotein is present in trans. [7] Although the protein is not found in mature virions, there is some evidence that it can be secreted from infected cells, even before viral exit, and taken up by neighboring uninfected cells. [9]

Agnoprotein has been associated with a number of processes in the viral life cycle, including transcription, replication, and encapsidation of the viral genome. [4] It has also been suggested that agnoprotein functions as a viroporin – that is, a viral protein that alters membrane permeability to facilitate the virus particles' exit from the cell. [10] In addition, effects on the behavior of the host cell itself have been observed, including impaired progression through the cell cycle and deficiencies in DNA repair. [2]

Because it is highly basic, agnoprotein has been suspected to be a DNA-binding protein, [6] but has not been shown to bind DNA. [2] A large number of protein-protein interactions have been reported between agnoprotein and other proteins of both viral and host cell origin. Agnoprotein interacts with the viral proteins small tumor antigen and large tumor antigen as well as with the capsid protein VP1. [2] Host cell proteins reported as binding partners for at least one virus species' agnoprotein include p53, Ku70, PP2A, YB-1, FEZ1, HP1α, α-SNAP, PCNA, and AP-3. [2] [3]

In some cases, the agnogene itself has functional significance, even if it cannot express agnoprotein. [2] [11] Deletion of the nucleotides in this region has been associated with a variant JC virus capable of infecting cell types not normally targeted by this virus. This variant has been associated with a disease recently described from case reports called JC virus encephalopathy, distinct from progressive multifocal leukoencephalopathy (PML), which has long been associated with JC in immunocompromised individuals. [12] [13]

Evolution

Although agnoprotein is critical for proliferation in the polyomaviruses in which it occurs, its distribution among polyomaviruses whose genomes have been sequenced is patchy. It has been well studied in three viruses that infect mammalian hosts, including two human viruses – BK virus and JC virus – and the simian virus SV40; the BK, JC, and SV40 examples are by far the best-studied and have fairly high sequence conservation. [2] [3] Additional predicted agnogenes have been identified from the sequenced genomes of other polyomaviruses, and the predicted protein products vary considerably in length and have low sequence identity overall. [3]

The distribution of agnoprotein among polyomaviruses has prompted speculation that there is little evolutionary selection pressure in favor of its presence. Among sequenced BK virus genomes, agnoprotein is the most variable viral protein in amino acid sequence. [3] Differences in tissue tropism and in viral life cycle, particularly in viral exit from the host cell, have also been proposed as explanations for the presence or absence of agnoprotein in various human polyomaviruses. [14]

Avian polyomaviruses

A gene occurs in avian polyomaviruses in a similar genomic position and was originally annotated as an agnogene, but it has no detectable sequence similarity to the mammalian examples. The protein product of this gene has been detected in the capsids of mature virions, leading to its reclassification as VP4 to reflect its distinct role as a structural protein. However, it is still often referred to as "avian agnoprotein 1a". [3] [15]

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 has the potential to cause 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.

<i>Human polyomavirus 2</i> Species of virus

Human polyomavirus 2, commonly referred to as the JC virus or John Cunningham virus, is a type of human polyomavirus. It was identified by electron microscopy in 1965 by ZuRhein and Chou, and by Silverman and Rubinstein, and later isolated in culture and named using the two initials of a patient, John Cunningham, with progressive multifocal leukoencephalopathy (PML). The virus causes PML and other diseases only in cases of immunodeficiency, as in AIDS or during treatment with immunosuppressive drugs.

<span class="mw-page-title-main">Arenavirus</span> Family of RNA viruses

An arenavirus is a bisegmented ambisense RNA virus that is a member of the family Arenaviridae. These viruses infect rodents and occasionally humans. A class of novel, highly divergent arenaviruses, properly known as reptarenaviruses, have also been discovered which infect snakes to produce inclusion body disease. At least eight arenaviruses are known to cause human disease. The diseases derived from arenaviruses range in severity. Aseptic meningitis, a severe human disease that causes inflammation covering the brain and spinal cord, can arise from the lymphocytic choriomeningitis virus. Hemorrhagic fever syndromes, including Lassa fever, are derived from infections such as Guanarito virus, Junin virus, Lassa virus, Lujo virus, Machupo virus, Sabia virus, or Whitewater Arroyo virus. Because of the epidemiological association with rodents, some arenaviruses and bunyaviruses are designated as roboviruses.

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 may be transmitted by a respiratory route. But it also can be found shedding from healthy skin, and in gastrointestinal tract tissues and elsewhere, and so 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.

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 9 (HPyV9) is a virus of the polyomavirus family that infects human hosts. It was discovered in 2011 and is a component of the skin flora in healthy adults.

Sorex araneus polyomavirus 1, formerly known as Human polyomavirus 12 (HPyV12), is a virus of the polyomavirus family that was first identified in human hosts and also infects shrews. It was discovered and reported in 2013 after isolation from the organs of the gastrointestinal tract, particularly the liver. The virus was renamed to Sorex araneus polyomavirus 1 in 2018, after discovery of the same virus in shrews. Infecting multiple hosts is rare among mammalian polyomaviruses.

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.

<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.

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

The small tumor antigen 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. 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.

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

  1. 1 2 Coric P, Saribas AS, Abou-Gharbia M, Childers W, White MK, Bouaziz S, Safak M (June 2014). "Nuclear magnetic resonance structure revealed that the human polyomavirus JC virus agnoprotein contains an α-helix encompassing the Leu/Ile/Phe-rich domain". Journal of Virology. 88 (12): 6556–75. doi:10.1128/jvi.00146-14. PMC   4054343 . PMID   24672035.
  2. 1 2 3 4 5 6 7 8 9 10 11 Saribas AS, Coric P, Hamazaspyan A, Davis W, Axman R, White MK, Abou-Gharbia M, Childers W, Condra JH, Bouaziz S, Safak M (October 2016). "Emerging From the Unknown: Structural and Functional Features of Agnoprotein of Polyomaviruses". Journal of Cellular Physiology. 231 (10): 2115–27. doi:10.1002/jcp.25329. PMC   5217748 . PMID   26831433.
  3. 1 2 3 4 5 6 7 8 Gerits N, Moens U (October 2012). "Agnoprotein of mammalian polyomaviruses". Virology. 432 (2): 316–26. doi: 10.1016/j.virol.2012.05.024 . PMC   7111918 . PMID   22726243.
  4. 1 2 3 Sami Saribas A, Abou-Gharbia M, Childers W, Sariyer IK, White MK, Safak M (August 2013). "Essential roles of Leu/Ile/Phe-rich domain of JC virus agnoprotein in dimer/oligomer formation, protein stability and splicing of viral transcripts". Virology. 443 (1): 161–76. doi:10.1016/j.virol.2013.05.003. PMC   3777628 . PMID   23747198.
  5. ↑ Wharton KA, Quigley C, Themeles M, Dunstan RW, Doyle K, Cahir-McFarland E, Wei J, Buko A, Reid CE, Sun C, Carmillo P, Sur G, Carulli JP, Mansfield KG, Westmoreland SV, Staugaitis SM, Fox RJ, Meier W, Goelz SE (18 May 2016). "JC Polyomavirus Abundance and Distribution in Progressive Multifocal Leukoencephalopathy (PML) Brain Tissue Implicates Myelin Sheath in Intracerebral Dissemination of Infection". PLOS ONE. 11 (5): e0155897. Bibcode:2016PLoSO..1155897W. doi: 10.1371/journal.pone.0155897 . PMC   4871437 . PMID   27191595.
  6. 1 2 Jay G, Nomura S, Anderson CW, Khoury G (May 1981). "Identification of the SV40 agnogene product: a DNA binding protein". Nature. 291 (5813): 346–9. Bibcode:1981Natur.291..346J. doi:10.1038/291346a0. PMID   6262654. S2CID   4266856.
  7. 1 2 Myhre MR, Olsen GH, Gosert R, Hirsch HH, Rinaldo CH (March 2010). "Clinical polyomavirus BK variants with agnogene deletion are non-functional but rescued by trans-complementation". Virology. 398 (1): 12–20. doi: 10.1016/j.virol.2009.11.029 . PMID   20005552.
  8. ↑ Sariyer IK, Saribas AS, White MK, Safak M (May 2011). "Infection by agnoprotein-negative mutants of polyomavirus JC and SV40 results in the release of virions that are mostly deficient in DNA content". Virology Journal. 8 (1): 255. doi:10.1186/1743-422X-8-255. PMC   3127838 . PMID   21609431.
  9. ↑ Otlu O, De Simone FI, Otalora YL, Khalili K, Sariyer IK (November 2014). "The agnoprotein of polyomavirus JC is released by infected cells: evidence for its cellular uptake by uninfected neighboring cells". Virology. 468–470: 88–95. doi:10.1016/j.virol.2014.07.054. PMC   4254181 . PMID   25151063.
  10. ↑ Suzuki T, Orba Y, Okada Y, Sunden Y, Kimura T, Tanaka S, Nagashima K, Hall WW, Sawa H (March 2010). "The human polyoma JC virus agnoprotein acts as a viroporin". PLOS Pathogens. 6 (3): e1000801. doi:10.1371/journal.ppat.1000801. PMC   2837404 . PMID   20300659.
  11. ↑ Khalili K, White MK, Sawa H, Nagashima K, Safak M (July 2005). "The agnoprotein of polyomaviruses: a multifunctional auxiliary protein". Journal of Cellular Physiology. 204 (1): 1–7. doi: 10.1002/jcp.20266 . PMID   15573377.
  12. ↑ Wüthrich C, Dang X, Westmoreland S, McKay J, Maheshwari A, Anderson MP, Ropper AH, Viscidi RP, Koralnik IJ (June 2009). "Fulminant JC virus encephalopathy with productive infection of cortical pyramidal neurons". Annals of Neurology. 65 (6): 742–8. doi:10.1002/ana.21619. PMC   2865689 . PMID   19557867.
  13. ↑ Dang X, Wüthrich C, Gordon J, Sawa H, Koralnik IJ (19 April 2012). "JC virus encephalopathy is associated with a novel agnoprotein-deletion JCV variant". PLOS ONE. 7 (4): e35793. Bibcode:2012PLoSO...735793D. doi: 10.1371/journal.pone.0035793 . PMC   3334910 . PMID   22536439.
  14. ↑ Van Ghelue M, Khan MT, Ehlers B, Moens U (November 2012). "Genome analysis of the new human polyomaviruses". Reviews in Medical Virology. 22 (6): 354–77. doi: 10.1002/rmv.1711 . PMID   22461085.
  15. ↑ Johne R, Müller H (April 2001). "Avian polyomavirus agnoprotein 1a is incorporated into the virus particle as a fourth structural protein, VP4". The Journal of General Virology. 82 (Pt 4): 909–18. doi: 10.1099/0022-1317-82-4-909 . PMID   11257197.
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