IHPI$O(*HP& - Inhibition de la transcription inverse du VIH-1 par la protéine Daxx

"#$$!&/'!6-!9#0'&62!)&!27/,/'#-0&!0*--6!1*62!&$&20&2!6-&!#0',@,'7!#-',@,2#8&!0*-'2&!6-!8#2J&!/1&0'2&!)&! @,26/!%B#,88&'!&'!M,/*8&!_`I34D! L’objectif de ma thèse était d’élucider le mécanisme par lequel Daxx ,-(,;&!8#!'2#-/02,1',*-!,-@&2/&!)6!FGH.I!/170,9,<6&+&-'D!C&/!27/68'#'/!127/&-'7/!,0,!ont d’abord montré! <6&!0&''&!#0',@,'7!)71&-)#,'!)&!8#!27J,*-!OGB!positionnée à l’e$'27+,'7!N.'&2+,-#8&!)&!"#$$D!N&!9#0'&62! 7'#-'! 6-&! 12*'7,-&! 0(#1&2*--&! /#-/! #0',@,'7! &-[>+#',<6&! 0*--6&5! 0&/! )*--7&/! /6JJ72#,&-'! 6-&! interaction entre Daxx et une protéine SUMOylée. Par l’étude de l’interactome de Daxx, nous avons +*-'27!<6&!"#$$!/&!8,&!E!8#!N>1K!)&/!0#1/,)&/!@,2#8&/!&-'2#-'&/!)&!+#-,R2&!OGB.)71&-)#-'&5!)&!9#:*-! E!9*2+&2!6-!0*+18&$&!+68',12*'7,<6&!0*-/','67!)&!SLGBTα5!SLGBUV5!&'!SMAQUD!"#$$!2&'#2)&!#8*2/!8#! )70#1/,)#',*-!&'!,-)6,'!6-&! ,-(,;,',*-!)&! 8#!'2#-/02,1',*-!,-@&2/&D!N&''&!7'6)&!12*1*/&! 6-!-*6@&#6! +70#-,/+&! jusqu’alors inconnu! )#-/! 8&<6&8! "#$$! =*6&! 6-! 2e8&! #-',@,2#8D! N&/! '2#@#6$! ,886/'2&-'! 7J#8&+&-'!8&!9#,'!<6&!8#!'2#-/02,1',*-!,-@&2/&!&'!8#!)70#1/,)#',*-!/*-'!)&6$!12*0&//6/!,-'&2)71&-)#-'/5! et que l’équilibre qui existe entre ces deu$!12*0&//6/!)*,'!W'2&!9,-&+&-'!27J6875!#6!2,/<6&!)&!1&2'62;&2! 8#!2718,0#',*-!@,2#8&D!S*6'&9*,/5!8e mécanisme que nous avons mis en évidence n’explique 1#/!E!86,!'*6'! seul l’ensemble des fonctions antivirales de Daxx5!&'!6-&!+&,88&62&!0*+127(&-/,*-!)&!8#!27J68#',*-!)&! 0&/!1(7-*+R-&/!1&2+&''2#,'!8#!+,/&!#6!1*,-'!)&!-*6@&88&/!/'2#'7J,&/!)&!86''&!&99,0#0&/!0*-'2&!8&!FGH. ID!

a-!&99&'5!8a fonction cellulaire principale de Daxx reste la répression transcriptionnelle. C’est d’ailleurs par cette activité qu’il exerc&!/*-!2e8&!#-',@,2#8!0*-'2&!6-!8#2J&!/1&0'2&!)&!@,26/!E!K"M!%B#,88&'!&'!M,/*8&! _Ì34D! G8! #! 7'7! +*-'27! <6&! "#$$! 1*6@#,'! ,nteragir avec l’intégrase du VIH.I5! 12*@*<6#-'! #,-/,! 8#! répression de l’expression des gènes viraux par l’intermédiaire du recrutement d’histones déacétyl#/&/! %H6#-J!&'!#8D!_``c4. C’est également par un mécanisme semblable que Daxx réprime 8#!'2#-/02,1',*-! )6!J7-*+&!)6!27'2*@,26/!KOF!%]2&J&2!&'!#8D!_``T4D!a-!*6'2&5!6-!#2',08&!+*-'2&!<6’une association )&! ABC5!6-!1#2'&-#,2&!0*--6!)&!"#$$5!#@&0!8&!12*@,26/!,-'7J27!12*@*<6&!/#!2712&//,*-!'2#-/02,1',*--&88&! %C6/,0!&'!#8D!_ÌU4D!N&/! )*--7&/!*-'! 7'7!1#2!8#!/6,'&!0*-9,2+7&/!1#2!d’autres!'2#@#6$!+*-'2#-'!<6&! 0&2'#,-&/!,/*9*2+&/!)&!ABC!#@#,&-'!8#!0#1#0,'7!)&!2712,+&2!8#!'2#-/02,1',*-!)&!8&-',@,26/!%B#/2**2,!&'! #8D!_Ì34D!K,-/,5!&-!,-'&2#J,//#-'!#@&0!8&/!(,/'*-&/!)7#07'>8#/&/5!"#$$!1*622#,'!,-)6,2&!)&/!+*),9,0#',*-/! 71,J7-7',<6&/! #6! -,@&#6! )6! 12*@,26/! #9,-! )&! 2712,+&2! 8#! '2#-/02,1',*-! )&/! JR-&/! @,2#6$5! 1#2',0,1#-'! #8*2/!E!8#!+,/&!&-!18#0&!*6!#6!+#,-',&-!)&!8#!8#'&-0&!)6!FGH.ID!En s’intégrant E!8#!0(2*+#',-&!)&!8#! 0&8868&.(e'&5!8&!FGH!1&2/,/'&!)#-/!),9972&-'/!'>1&/!0&8868#,2&/!),/1&2/7/!E!'2#@&2/!l’organisme5!jusqu’à 7'#;8,2!6-&!,-9&0',*-!8#'&-'&D!"#-/!0&!0*-'&$'&5!8&!12*@,26/!8#'&-'!&/'!'2#-/02,1',*--&88&+&-'!,-#0',95!0&! qui lui permet d’échapper à la détection par les cellules de l’immunitéD!B#8J27!6-&!&99,0#0,'7!0&2'#,-&!

IVV! NQMNCPOGQM! )&/!'2#,'&+&-'/!aujourd’hui disponibles!#;*6',//#-'!E!6-!0*-'2e8&!)&!8#!0(#2J&!@,2#8&!0(&[!8&/!1#',&-'/! ,-9&0'7/!&'!'2#,'7/5!8#!1&2/,/'#-0&!)&!27/&2@*,2/!)&!12*@,26/!8#'&-'/!0*-/','6&!6-!*;/'#08&!+#=&62!E!8#! guérison complète. L’une des stratégies envisagées!dans l’optique d’une clairance virale '*'#8&!&/'!0&88&! )6! p!/(*0s! #-)! s,88!qD! N&''&! #112*0(&! 0*-/,/'&! E! 27#0',@&2! 8&! 12*@,26/! 8#'&-'! #9,-! <6&! 8&/! 0&8868&/! infectées soit détectées puis détruites par l’organisme! %"&&s/! _Ì_4D! L’identification de molécules 2&J2*617&/! /*6/! 8&! -*+! )&! CLK! %C#'&-0>.2&@&2/,-J! #J&-'/4! &'! 12*@*<6#-'! 6-&! 27#0',@#',*-! '2#-/02,1',*--&88&!&99,0#0&!)6!J7-*+&!@,2#8!8#'&-'!fait l’objet d’une recherche intensive dans le cadre )6! )7@&8*11&+&-'! )&! '(72#1,&/! 062#',@&/D! Parmi ces molécules, les inhibiteurs d’(,/'*-&/! )7#07'>8#/&/5!constituent un champ de recherche prometteur, puisque l’inhibition de c&/!12*'7,-&/! /&+;8&!9#@*2,/&2!6-!2&;*-)!2#1,)&!du virus au sein de l’organisme!%L#/+6//&-!&'!#8D!_ÌVo!O„J##2)!&'! #8D! _ÌT4, même si ce traitement seul ne suffit pas à éradiquer l’ensemble des réservoirs v,2#6$! %H#/(&+,! &'! O#)*X/s,! _`_`4D! "#$$! 7'#-'! 6-! 1#2'&-#,2&! 12,@,87J,7! )&! 0&/! (,/'*-&/! )7#07'>8#/&/! &'! d’autres protéines imp8,<67&/!)#-/!8&!2&+*)&8#J&!)&!8#!0(2*+#',-&5!,8!1*622#,'!0*-/','6&2!6-&!0,;8&! ,-'72&//#-'&! 1*62! 8&! )7@&8*11&+&-'! )&! +*87068&/! '(72#1&6',<6&/! @,/#-'! E! &+1W0(&2! 8#! 8#'&-0&! )6! FGH.ID!C#!)7'&0',*-!&'! 8#!)&/'260',*-!)&/!27/&2@*,2/!)&! 8#'&-0&! )&+&62&-'!6-!&-=&6! +#=&62!)#-/!8#! J672,/*-!)&/!1#',&-'/!&'!)#-/!8&!0*-'2e8&!)&!8#!1#-)7+,&!<6,!0*-',-6&!)&!12*J2&//&2!0(#<6&!#--7&D! !

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Dans le document Inhibition de la transcription inverse du VIH-1 par la protéine Daxx (Page 144-186)