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Variant surface glycoprotein
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<h2 id="in-trypanosoma-brucei">In <i>Trypanosoma brucei</i></h2> <p>In <i>Trypanosoma brucei</i>, the cell surface is covered by a dense coat of ~5 million VSG <a href="/facts/Dimer_(biochemistry)/c8LwFJPG">dimers</a>,<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> ~90% of all cell surface protein and ~10% of total cell protein. </p><p>The properties of the VSG coat that enable immune evasion are: </p> <ul><li>Shielding – the dense nature of the VSG coat (VSG proteins pack shoulder-to-shoulder) prevents the immune system of the mammalian host from accessing the <a href="/facts/Cell_membrane/vAXSD0DT">plasma membrane</a> or any other parasitic invariant surface <a href="/facts/Epitopes/PL0oBuGh">epitopes</a> (such as <a href="/facts/Ion_channels/A46LARFH">ion channels</a>, <a href="/facts/Membrane_transporter/h1aczVxg">transporters</a>, <a href="/facts/Cell_receptor/tjTAC76a">receptors</a> etc.). The coat is uniform, made up of millions of copies of the same molecule; therefore, VSG is the only part of the trypanosome that the immune system can recognize.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a></li> <li>Periodic <a href="/facts/Antigenic_variation/4cQDTTX7">antigenic variation</a> – the VSG coat undergoes frequent <a href="/facts/Stochastic/uMbgL94r">stochastic</a> genetic modification—'switching'—allowing variants expressing a new VSG coat to escape the <a href="/facts/Adaptive_immunity/bc7zT1Jo">specific immune response</a> raised against the previous coat. This antigenic variation creates cyclical waves of parasitemia characteristic of Human African Trypanosomiasis.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a></li> <li>Antigen 'cleaning' and VSG recycling—VSG is efficiently recycled through the trypanosome flagellar pocket, allowing antibodies to be 'cleaned' from VSG before re-incorporation back into the cellular membrane. Importantly, VSGs recognized and bound by antibodies are selectively pushed toward the flagellar pocket at a quicker rate than unidentified VSG; in this scenario, the antibody acts as a 'sail', which quickens the process of VSG being brought to the area of recycling.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a></li></ul> <p>The VSGs from <i>T. brucei</i> are attached to the plasma membrane via a covalent attachment to two <a href="/facts/Glycosyl-phosphatidylinositol/dKsjvUTx">glycosyl-phosphatidylinositol</a> (GPI) anchors (one per <a href="/facts/Monomer/Gw3CltMb">monomer</a>),<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> which directs its forward-trafficking from the ER to the flagellar pocket for incorporation into the membrane, as predicted by the GPI valence hypothesis.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a><a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p><p>VSGs are replaced by an equally dense coat of <a href="/facts/Procyclin/xW8PeDn4">procyclins</a> when the parasite differentiates into the procyclic form in the <a href="/facts/Tsetse_fly/N4FAz2Wd">tsetse fly</a> midgut. There is a very fast inhibition of VSG gene transcription which occurs as soon as the temperature is lowered.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p> <h3>Expression</h3> <p>The source of VSG variability during infection is a large 'archive' of <i>VSG</i> genes present in the <i>T. brucei</i> <a href="/facts/Genome/tjhWET4V">genome</a>. Some of these are full-length, intact <a href="/facts/Genes/e1swwPY6">genes</a>; others are <a href="/facts/Pseudogene/VfbL4L07">pseudogenes</a> (typically with <a href="/facts/Frameshift_mutations/ncWrMHqm">frameshift mutations</a>, premature <a href="/facts/Stop_codons/1yuAkq9X">stop codons</a>, or fragmentation).<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> Expression of an antigenically different VSG can occur by simply switching to a different full-length <i>VSG</i> gene by Expression Site switching (switching which ES is active). In addition, <a href="/facts/Chimeric_gene/rXJyuTQ3">chimeric</a> or 'mosaic' <i>VSG</i> genes can be generated by combining segments from more than one silent <i>VSG</i> gene. The formation of mosaic <i>VSG</i>s allows the (partial) expression of pseudogene <i>VSG</i>s, which can constitute the major portion of the <i>VSG</i> archive, and can contribute directly to antigenic variation, vastly increasing the trypanosome's capacity for immune evasion and posing a major problem for <a href="/facts/Vaccine/QcXzLug2">vaccine</a> development.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p><p><i>VSG</i> genes can be kept <a href="/facts/Gene_silencing/mh0JYYPD">silent</a> and switched on at any given time. The expressed <i>VSG</i> is always located in an Expression Site (ES), which are specialised expression <a href="/facts/Locus_(genetics)/JcIT8wLm">loci</a> found at the <a href="/facts/Telomeres/RQ4Gp9LT">telomeres</a> of some of the large and intermediate chromosomes. Each ES is a polycistronic unit, containing a number of Expression Site-Associated Genes (ESAGs) all expressed along with the active VSG. While multiple ES exist, only a single one is ever active at one time. A number of mechanisms appear to be involved in this process, but the exact nature of the silencing is still unclear.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p><p>The expressed VSG can be switched either by activating a different expression site (and thus changing to express the <i>VSG</i> in that site), or by changing the <i>VSG</i> gene in the active site to a different variant. The genome contains many copies of VSG genes, both on minichromosomes and in repeated sections in the interior of the chromosomes. These are generally silent, typically with omitted sections or premature stop codons, but are important in the evolution of new VSG genes. It is estimated up to 10% of the <i>T.brucei</i> genome may be made up of VSG genes or <a href="/facts/Pseudogenes/VfbL4L07">pseudogenes</a>. Any of these genes can be moved into the active site by <a href="/facts/Genetic_recombination/uocNH0m7">recombination</a> for expression. Again, the exact mechanisms that control this are unclear, but the process seems to rely on <a href="/facts/DNA_repair/hsURuYYq">DNA repair</a> machinery and a process of <a href="/facts/Homologous_recombination/WU0IIVVv">homologous recombination</a>.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p><p>The bloodstream expression site (BES), or telomeric expression site, is used for exchanging variant surface glycoproteins when in host's blood stream to escape the <a href="/facts/Complement_system/vRSrQDUv">complement system</a>. BESs are polymorphic in size and structure but reveal a surprisingly conserved architecture in the context of extensive recombination. Very small BESs do exist and many functioning BESs do not contain the full complement of <i>expression site associated genes</i> (ESAGs).<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> There is a collection of an estimated 20-30 sites, each being active at a time.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> Active VSG expression sites are depleted of <a href="/facts/Nucleosome/HX5DR9bn">nucleosomes</a>.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> </p><p>The gene repertoires in <i>T. brucei</i> have diverged to become strain-specific.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p><p>The variant surface glycoprotein genes of <i>T. brucei</i> have been classified into two groups depending upon whether or not duplication of the genes is observed when they are expressed.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> </p> <h3>Secretory trafficking</h3> <p><i>Trypanosoma</i> have a simple, polarized membrane transport system consisting of a single <a href="/facts/Endoplasmic_reticulum/DVbLA7GE">ER</a>, <a href="/facts/Lysosome/0mcrzJU9">lysosome</a>, and <a href="/facts/Golgi_apparatus/F91pGb3t">Golgi apparatus</a>. </p><p>VSG is first transcribed as a polycistron and then undergoes trypanosomatid-specific <a href="/facts/Polyadenylation/ILnXUBKP">poly-adenylation</a> and <a href="/facts/Trans-splicing/5os2Tyud">trans-splicing</a> directed by <a href="/facts/Polypyrimidine_tract/CACEVNWl">polypyrimidine tracts</a>. Because there is no transcriptional control, the VSG <a href="/facts/Three_prime_untranslated_region/wB0oYfKd">3'UTR</a> is important for its RNA stability (most importantly, the 8mer and 14mer). VSG is then transcribed on membrane-bound <a href="/facts/Polysome/jHlMBu8W">polysomes</a>, and the appearance of the N-terminal signal sequence directs VSG to the ER. VSG is thereby co-translationally transported into the ER lumen, rapidly <a href="/facts/N-linked_glycosylation/7W9cDU3q">N-glycosylated</a> (on asn-x-ser/thr sites) and <a href="/facts/Glycosylphosphatidylinositol/dKsjvUTx">GPI anchored</a> at the ω site by a <a href="/facts/Transamination/Ntj23r8y">transamination</a> reaction (removing of the C-term hydrophobic 17 or 23 aa GPI anchoring sequence). The ω site is always Ser (usually in 17 aa signal sequence peptides), Asp (usually in 23 aa signal sequence peptides), or Asn. Also, the number of <a href="/facts/N-glycosylation/7W9cDU3q">N-glycosylation</a> sites per VSG may vary (usually 1-3 N-glycans). VSG MITat.1.5 is glycosylated at all three potential N-glycosylation sites.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> </p><p>VSG then undergoes the <a href="/facts/Calreticulin_protein_family/uNtFnbAP">calreticulin</a>/<a href="/facts/Calnexin/HIxteHTD">calnexin</a> folding cycle (calnexin is absent in <i>Trypanosoma brucei</i>), where it is transiently monoglucosylated and deglucosylated, and interacts with various ER chaperone proteins, such as BiP, in order to fold correctly. VSG efficiently folds and dimerizes (suggesting intrinsically favorable folding) and is transported through the Golgi to the flagellar pocket for incorporation into the cell membrane. </p><p>Importantly, following incorporation into the cellular membrane, VSG may later be recycled through the flagellar pocket and sorted back to the cell surface. VSG is not turned over by lysosomal or proteasomal canonical degradation pathways,<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> but is instead lost from the cell by specific cleavage of its GPI anchor by GPI-specific <a href="/facts/Phospholipase_C/Cuo6V7gU">PLC</a>. </p> <h3>Structure</h3> <p>VSG genes are hugely variable at the <a href="/facts/DNA_sequencing/hsPsNCQW">sequence</a> (primary) level, but variants are thought to have strongly conserved <a href="/facts/Protein_structure/BptnTs9X">structural</a> (tertiary) features, based on two determined 3-dimensional structures<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> and conservation of 2-dimensional sequence motifs (descending and ascending alpha-helices that make up the dimerization interface), allowing them to perform a similar shielding function.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> VSGs are made up of <a href="/facts/N-terminus/yKYpuaBJ">N terminal</a> <a href="/facts/Protein_domain/oUpFcSsl">domain</a> of around 300–350 <a href="/facts/List_of_standard_amino_acids/xoXITvm0">amino acids</a> with low sequence homology (13–30% identity), and a more conserved <a href="/facts/C-terminus/ws4scHgT">C terminal</a> domain of ~100 amino acids. N-terminal domains are grouped into classes A-C depending on their cysteine patterns. C-term domains are grouped by sequence homology into classes I-III, with apparently no restriction on which N-term classes they can pair with to form a full VSG. To dimerize, VSG N-terminal domains form a bundle of four <a href="/facts/Alpha_helix/7CESPIYJ">alpha helices</a> directed by hydrophobic interactions, around which hang smaller structural features (five smaller helices and three beta-sheets). </p><p>VSG is anchored to the cell membrane via a <a href="/facts/Glycophosphatidylinositol/dKsjvUTx">glycophosphatidylinositol (GPI) anchor</a>—a noncovalent linkage from the C-terminus which directs its forward trafficking from the ER to the membrane. This GPI anchor is specifically cleaved by GPI Phospholipase C, cleaving the membrane-form VSG, and allowing VSG protein and portion of the GPI anchor to be lost into the extracellular milieu as soluble VSG (sVSG, which is can be recognized as Cross-Reacting Determinant, or CRD), while retaining the two 1,2-dimyristolglycerol chains in the membrane. </p> <h3>Antigenic variation</h3> <p>VSG is highly <a href="/facts/Immunogenic/QVxzK4tD">immunogenic</a>, and an <a href="/facts/Adaptive_immunity/bc7zT1Jo">immune response</a> raised against a specific VSG coat will rapidly kill trypanosomes expressing this variant. <a href="/facts/Antibody/MX8pdTdP">Antibody</a>-mediated trypanosome killing can also be observed <i><a href="/facts/In_vitro/evp3hAX6">in vitro</a></i> by a <a href="/facts/Complement_system/vRSrQDUv">complement-mediated</a> <a href="/facts/Lysis/th8pXeEn">lysis</a> <a href="/facts/Assay/fPUYjx1I">assay</a>. However, with each <a href="/facts/Cell_division/n5MrunWj">cell division</a> there is a possibility that one or both of the <a href="/facts/Offspring/v7LD4qBl">progeny</a> will switch expression to change the VSG that is being expressed. The frequency of VSG switching has been measured to be approximately 0.1% per division,<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> though switching rates do differ in culture vs. <i>in vivo</i>. As <i>T. brucei</i> populations can peak at a size of 1011 within a host<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> this rapid rate of switching ensures that the parasite population is constantly diverse. A diverse range of coats expressed by the trypanosome population means that the immune system is always one step behind: it takes several days for an immune response against a given VSG to develop, giving the population time to diversify as individuals undergo further switching events. Reiteration of this process prevents extinction of the infecting trypanosome population, allowing chronic persistence of parasites in the host, enhancing opportunities for transmission. The clinical effect of this cycle is successive 'waves' of parasitaemia (trypanosomes in the blood).<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> </p> <h2 id="in-other-trypanosomes">In other trypanosomes</h2> <p>Variable surface glycoproteins are also found in other <i><a href="/facts/Trypanosoma/8FQEE2VL">Trypanosoma</a></i> species. </p><p>In <i><a href="/facts/Trypanosoma_equiperdum/ntQkpnQw">Trypanosoma equiperdum</a></i>, a parasite causing the <a href="/facts/Covering_sickness/LEqJQsJy">covering sickness</a> in horses, these proteins allow the parasite to efficiently evade the host animal's immune system.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> These VSGs allow the organism to constantly manipulate and change the surface structure of its proteins, which means it is constantly being presented to the immune system as a new foreign organism and this prevents the body from mounting a large enough immune response to eradicate the disease.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> In this sense, <i>Trypanosoma equiperdum</i> is a very efficient organism; it may infect fewer species than other diseases, but it infects and survives very efficiently within its specified hosts. The VSG proteins in <i>T. equiperdum</i> are also <a href="/facts/Phosphorylated/LXUEEeIL">phosphorylated</a>.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> </p><p>A VSG gene from <i><a href="/facts/Trypanosoma_evansi/xj3xvtqA">Trypanosoma evansi</a></i>, a parasite that causes a form of <a href="/facts/Surra/FgzkkMBk">surra</a> in animals, has been cloned in <i><a href="/facts/Escherichia_coli/nR4Gvl56">Escherichia coli</a></i>. The expressed protein is <a href="/facts/Immunoreactive/eHo2YM9S">immunoreactive</a> with all the sera combinations. The animals immunized with whole cell lysate or recombinant protein show similar antibody reactions in <a href="/facts/ELISA/8yvpYDtH">ELISA</a> (enzyme-linked immunosorbent assay) and CATT (<a href="/facts/Agglutination_(biology)/MlUfom8Y">card agglutination test for trypanosomiasis</a>).<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> The variable surface glycoprotein RoTat 1.2 <a href="/facts/Polymerase_chain_reaction/G0jWzJy1">PCR</a> can be used as a specific diagnostic tool for the detection of <i>T. evansi</i> infections.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> </p><p>The smallest VSG protein (40 kDa in size) to date (1996) has been found in <i><a href="/facts/Trypanosoma_vivax/xAnplj6R">Trypanosoma vivax</a></i>, which bears little carbohydrate.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> </p><p>In <i><a href="/facts/Trypanosoma_congolense/Bw92uGK5">Trypanosoma congolense</a></i>, <i>in vitro</i> analyses of the incorporated sugars after hydrolysis of the glycoprotein showed that <a href="/facts/Glucosamine/HKCp9hoR">glucosamine</a> and <a href="/facts/Mannose/U05bJ7p8">mannose</a> are utilized in the biosynthesis of the carbohydrate moiety directly whereas galactose was converted possibly to other intermediates before being incorporated into the antigen. The unglycosylated VSG with a molecular weight of 47 kDa had completely lost its size heterogeneity.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li>Amastin, another surface (trans-membrane) glycoprotein in trypanosomatid parasites<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a></li> <li><a href="/facts/Coat_protein_(disambiguation)/LlkFdeMV">Coat protein (disambiguation)</a></li> <li><a href="/facts/Glycocalyx/mozTP4zq">Glycocalyx</a></li> <li><a href="/facts/List_of_MeSH_codes_(D23)/PchMBMqW">List of MeSH codes (D23)</a></li> <li><a href="/facts/List_of_MeSH_codes_(D12.776.395)/Gpe5e4nh">List of MeSH codes (D12.776.395)</a></li> <li><a href="/facts/List_of_MeSH_codes_(D12.776.543)/j0wtW1Ls">List of MeSH codes (D12.776.543)</a></li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://meshb.nlm.nih.gov/record/ui?name=Variant+Surface+Glycoproteins%2C+Trypanosoma">Variant Surface Glycoproteins, Trypanosoma</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li> <li><a href="http://www.icp.ucl.ac.be/~opperd/parasites/vsg.htm">www.icp.ucl.ac.be</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Cross GA (1975). "Identification, purification and properties of clone-specific glycoprotein antigens constituting the surface coat of Trypanosoma brucei". Parasitology. 71 (3): 393–417. doi:10.1017/s003118200004717x. PMID 645. S2CID 20749130. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Buck GA, Jacquemot C, Baltz T, Eisen H (December 1984). "Re-expression of an inactivated variable surface glycoprotein gene in Trypanosoma equiperdum". Gene. 32 (3): 329–36. doi:10.1016/0378-1119(84)90008-8. PMID 6530143. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Barry JD, McCulloch R (2001). "Antigenic variation in trypanosomes: enhanced phenotypic variation in a eukaryotic parasite". Advances in Parasitology Volume 49. Vol. 49. pp. 1–70. doi:10.1016/S0065-308X(01)49037-3. ISBN 978-0-12-031749-3. PMID 11461029. {{cite book}}: |journal= ignored (help) <a href="978-0-12-031749-3" target="_blank">978-0-12-031749-3</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Overath P, Chaudhri M, Steverding D, Ziegelbauer K (February 1994). "Invariant surface proteins in bloodstream forms of Trypanosoma brucei". Parasitology Today. 10 (2): 53–8. doi:10.1016/0169-4758(94)90393-X. PMID 15275499. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Ross R, Thomson D (June 1910). "A Case of Sleeping Sickness showing Regular Periodical Increase of the Parasites Disclosed". British Medical Journal. 1 (2582): 1544–5. doi:10.1136/bmj.1.2582.1544. PMC 2331906. PMID 20765166. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2331906" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2331906</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Rudenko G (2011-10-24). "African trypanosomes: the genome and adaptations for immune evasion". Essays in Biochemistry. 51: 47–62. doi:10.1042/bse0510047. PMID 22023441. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Grab DJ, Verjee Y. "Localization of a Variable Surface Glycoprotein Phosphatidylinositol-Specific Phospholipase-C in Trypanosoma brucei brucei". FAO Corporate document depository. Food and Agricultural Organization of the United Nations. Archived from the original on 2018-08-31. Retrieved 2013-07-28. <a href="https://web.archive.org/web/20180831104205/http://www.fao.org/wairdocs/ilri/x5550e/x5550e0e.htm" target="_blank">https://web.archive.org/web/20180831104205/http://www.fao.org/wairdocs/ilri/x5550e/x5550e0e.htm</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Triggs VP, Bangs JD (February 2003). "Glycosylphosphatidylinositol-dependent protein trafficking in bloodstream stage Trypanosoma brucei". Eukaryotic Cell. 2 (1): 76–83. doi:10.1128/ec.2.1.76-83.2003. PMC 141176. PMID 12582124. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC141176" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC141176</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Schwartz KJ, Peck RF, Tazeh NN, Bangs JD (December 2005). "GPI valence and the fate of secretory membrane proteins in African trypanosomes". Journal of Cell Science. 118 (Pt 23): 5499–511. doi:10.1242/jcs.02667. 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