Oligosaccharyltransferase

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Tumor cells have been able to alter the subunits of OST to use N-glycosylation to their advantage for immune evasion. Tumor cells have the ability to inactive T cells having a programmed death-ligand 1 (PD-L1) which binds to the programmed death (PD-1) receptor of the T Cell. This allows the tumor cell to evade the PD-L1 immune response checkpoint going unnoticed. The PD-L1 is a transmembrane protein with 4 sites available for N-glycosylation. The glycosylation of these sites prevents phosphorylation of the protein ensuring the expression of the protein on the outside of tumor cells. Tumor cells also have a process, epithelial-to-mesenchymal transition (EMT), which helps the cell acquire invasive properties by altering protein expression profiles<ref name="tumor1">DOI:10.3390/ijms20236074<ref/> This EMT process has the ability to upregulate the expression of PD-L1 along the catalytic subunits of OST, STT3A and STT3B. The increased regulation of PD-L1 allows for more of these proteins to undergo glycosylation further ensuring their cell surface expression. EMT also has the ability to promote glycosyltransferases in their formation of poly-N-acetyllactosamine thich proves to be essential in the binding of PD-L1 to PD-1 of T cells. This discovery suggests EMT reprograms OST to carry out this upregulation establishing PD-L1-mediated immune escape<ref name="tumor1"/>.
Tumor cells have been able to alter the subunits of OST to use N-glycosylation to their advantage for immune evasion. Tumor cells have the ability to inactive T cells having a programmed death-ligand 1 (PD-L1) which binds to the programmed death (PD-1) receptor of the T Cell. This allows the tumor cell to evade the PD-L1 immune response checkpoint going unnoticed. The PD-L1 is a transmembrane protein with 4 sites available for N-glycosylation. The glycosylation of these sites prevents phosphorylation of the protein ensuring the expression of the protein on the outside of tumor cells. Tumor cells also have a process, epithelial-to-mesenchymal transition (EMT), which helps the cell acquire invasive properties by altering protein expression profiles<ref name="tumor1">DOI:10.3390/ijms20236074<ref/> This EMT process has the ability to upregulate the expression of PD-L1 along the catalytic subunits of OST, STT3A and STT3B. The increased regulation of PD-L1 allows for more of these proteins to undergo glycosylation further ensuring their cell surface expression. EMT also has the ability to promote glycosyltransferases in their formation of poly-N-acetyllactosamine thich proves to be essential in the binding of PD-L1 to PD-1 of T cells. This discovery suggests EMT reprograms OST to carry out this upregulation establishing PD-L1-mediated immune escape<ref name="tumor1"/>.
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<scene name='91/910721/Pd-l1_ribosome_inactivating/1'>PD-L1</scene>
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PD-L1
Although the cell context-dependent abilities of the OST make the complex favorable for tumor progression, this proves to be a possible route for inhibition of tumor growth. Currently there are no known drugs which targets N-glycosylation. There are current studies that have developed N-glycosylation inhibition which has progressed what we know about the relevance of OST in cancer treatment. An inhibitor called N-glycosylation inhibitor 1 (NGI-1) has been discovered which has the ability prevent N-glycosylation stopping the function of an inactivated form of a luciferase mutant (ERLucT)<ref name="tumor1"/>. This inhibitor has the ability to inhibit the catalytic function of both catalytic subunits of OST favoring STT3B. Studying NGI-1 further will hopefully lead to the development of treatments which can prevent tumor growth where current drugs and medications fail.
Although the cell context-dependent abilities of the OST make the complex favorable for tumor progression, this proves to be a possible route for inhibition of tumor growth. Currently there are no known drugs which targets N-glycosylation. There are current studies that have developed N-glycosylation inhibition which has progressed what we know about the relevance of OST in cancer treatment. An inhibitor called N-glycosylation inhibitor 1 (NGI-1) has been discovered which has the ability prevent N-glycosylation stopping the function of an inactivated form of a luciferase mutant (ERLucT)<ref name="tumor1"/>. This inhibitor has the ability to inhibit the catalytic function of both catalytic subunits of OST favoring STT3B. Studying NGI-1 further will hopefully lead to the development of treatments which can prevent tumor growth where current drugs and medications fail.

Revision as of 18:26, 26 April 2022

Oligosaccharyltransferase

Oligosaccharyltransferase

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References

  1. ↑ 1.0 1.1 doi: https://dx.doi.org/10.2210/rcsb_pdb/mom_2022_2
  2. ↑ 2.0 2.1 Mohanty S, Chaudhary BP, Zoetewey D. Structural Insight into the Mechanism of N-Linked Glycosylation by Oligosaccharyltransferase. Biomolecules. 2020 Apr 17;10(4). pii: biom10040624. doi: 10.3390/biom10040624. PMID:32316603 doi:http://dx.doi.org/10.3390/biom10040624
  3. ↑ Ramirez AS, Kowal J, Locher KP. Cryo-electron microscopy structures of human oligosaccharyltransferase complexes OST-A and OST-B. Science. 2019 Dec 13;366(6471):1372-1375. doi: 10.1126/science.aaz3505. PMID:31831667 doi:http://dx.doi.org/10.1126/science.aaz3505
  4. ↑ doi: https://dx.doi.org/10.3390/ijms20236074<ref></ref>ThisEMTprocesshastheabilitytoupregulatetheexpressionofPD-L1alongthecatalyticsubunitsofOST,STT3AandSTT3B.TheincreasedregulationofPD-L1allowsformoreoftheseproteinstoundergoglycosylationfurtherensuringtheircellsurfaceexpression.EMTalsohastheabilitytopromoteglycosyltransferasesintheirformationofpoly-N-acetyllactosaminethichprovestobeessentialinthebindingofPD-L1toPD-1ofTcells.ThisdiscoverysuggestsEMTreprogramsOSTtocarryoutthisupregulationestablishingPD-L1-mediatedimmuneescape<refname="tumor1"/>.PD-L1Althoughthecellcontext-dependentabilitiesoftheOSTmakethecomplexfavorablefortumorprogression,thisprovestobeapossiblerouteforinhibitionoftumorgrowth.CurrentlytherearenoknowndrugswhichtargetsN-glycosylation.TherearecurrentstudiesthathavedevelopedN-glycosylationinhibitionwhichhasprogressedwhatweknowabouttherelevanceofOSTincancertreatment.AninhibitorcalledN-glycosylationinhibitor1(NGI-1)hasbeendiscoveredwhichhastheabilitypreventN-glycosylationstoppingthefunctionofaninactivatedformofaluciferasemutant(ERLucT)<refname="tumor1"/>.ThisinhibitorhastheabilitytoinhibitthecatalyticfunctionofbothcatalyticsubunitsofOSTfavoringSTT3B.StudyingNGI-1furtherwillhopefullyleadtothedevelopmentoftreatmentswhichcanpreventtumorgrowthwherecurrentdrugsandmedicationsfail.==Viruses==Wecurrentlyareamidstaneverendingwar.Thiswarexistswithvirusesandhasbeenoccurringsincethestartofalllivingthingsandiscenteredgreatlyaroundglycosylatedproteins.Ourcellsareconstantlyevolvingtodevelopdifferentfeaturestoprotectagainstviruses,whileitistheirgoaltodevelopabilitiestoevadeourdefenses.Onewayourcellshadpreventedviralpathogensfrominfectionwastheuseofcellsurfacecarbohydratesto,inasense,flyundertheirradar.Howeverviruseshadevolvedtorecognizethesecarbohydratesandtargetthesecellsforinfection.Thankfullyourimmunesystemisequallyuptospeedasithassinceevolvedtorecognizecertainglycosylatedlipidsandproteinsthatthevirushasacquiredafterhijackingahostcell.intextcitation.<refname="pdb101"/>ThisisasamplescenecreatedwithSATto<scenename="/12/3456/Sample/1">color</scene>byGroup,andanothertomake<scenename="/12/3456/Sample/2">atransparentrepresentation</scene>oftheprotein.YoucanmakeyourownscenesonSATstartingfromscratchorloadingandeditingoneofthesesamplescenes.

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