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Hijacking of the O-GlcNAcZYME complex by the HTLV-1 Tax oncoprotein facilitates viral transcription
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نویسنده
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groussaud d. ,khair m. ,tollenaere a.i. ,waast l. ,kuo m.-s. ,mangeney m. ,martella c. ,fardini y. ,coste s. ,souidi m. ,benit l. ,pique c. ,issad t.
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منبع
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plos pathogens - 2017 - دوره : 13 - شماره : 7
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چکیده
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The viral tax oncoprotein plays a key role in both human t-cell lymphotropic virus type 1 (htlv-1)-replication and htlv-1-associated pathologies,notably adult t-cell leukemia. tax governs the transcription from the viral 5’ltr,enhancing thereby its own expression,via the recruitment of dimers of phosphorylated creb to camp-response elements located within the u3 region (vcre). in addition to phosphorylation,creb is also the target of o-glcnacylation,another reversible post-translational modification involved in a wide range of diseases,including cancers. o-glcnacylation consists in the addition of o-linked-n-acetylglucosamine (o-glcnac) on serine or threonine residues,a process controlled by two enzymes: o-glcnac transferase (ogt),which transfers o-glcnac on proteins,and o-glcnacase (oga),which removes it. in this study,we investigated the status of o-glcnacylation enzymes in htlv-1-transformed t cells. we found that oga mrna and protein expression levels are increased in htlv-1-transformed t cells as compared to control t cell lines while ogt expression is unchanged. however,higher oga production coincides with a reduction in oga specific activity,showing that htlv-1-transformed t cells produce high level of a less active form of oga. introducing tax into hek-293t cells or tax-negative htlv-1-transformed tl-om1 t cells is sufficient to inhibit oga activity and increase total o-glcnacylation,without any change in ogt activity. furthermore,tax interacts with the ogt/oga complex and inhibits the activity of ogt-bound oga. pharmacological inhibition of oga increases creb o-glcnacylation as well as htlv-1-ltr transactivation by tax and creb recruitment to the ltr. moreover,overexpression of wild-type creb but not a creb protein mutated on a previously described o-glcnacylation site enhances tax-mediated ltr transactivation. finally,both ogt and oga are recruited to the ltr. these findings reveal the interplay between tax and the o-glcnacylation pathway and identify new key molecular actors involved in the assembly of the tax-dependent transactivation complex. © 2017 groussaud et al.
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آدرس
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inserm,u1016,institut cochin,paris,france,cnrs,umr8104,paris,france,université paris descartes,sorbonne paris cité,paris, France, inserm,u1016,institut cochin,paris,france,cnrs,umr8104,paris,france,université paris descartes,sorbonne paris cité,paris, France, inserm,u1016,institut cochin,paris,france,cnrs,umr8104,paris,france,université paris descartes,sorbonne paris cité,paris, France, inserm,u1016,institut cochin,paris,france,cnrs,umr8104,paris,france,université paris descartes,sorbonne paris cité,paris, France, inserm,u1016,institut cochin,paris,france,cnrs,umr8104,paris,france,université paris descartes,sorbonne paris cité,paris, France, inserm,u1016,institut cochin,paris,france,cnrs,umr8104,paris,france,université paris descartes,sorbonne paris cité,paris, France, inserm,u1016,institut cochin,paris,france,cnrs,umr8104,paris,france,université paris descartes,sorbonne paris cité,paris, France, inserm,u1016,institut cochin,paris,france,cnrs,umr8104,paris,france,université paris descartes,sorbonne paris cité,paris, France, inserm,u1016,institut cochin,paris,france,cnrs,umr8104,paris,france,université paris descartes,sorbonne paris cité,paris, France, inserm,u1016,institut cochin,paris,france,cnrs,umr8104,paris,france,université paris descartes,sorbonne paris cité,paris, France, inserm,u1016,institut cochin,paris,france,cnrs,umr8104,paris,france,université paris descartes,sorbonne paris cité,paris, France, inserm,u1016,institut cochin,paris,france,cnrs,umr8104,paris,france,université paris descartes,sorbonne paris cité,paris, France, inserm,u1016,institut cochin,paris,france,cnrs,umr8104,paris,france,université paris descartes,sorbonne paris cité,paris, France
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Authors
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