HAL Id: inserm-00137282
https://www.hal.inserm.fr/inserm-00137282
Submitted on 6 Dec 2007
HAL is a multi-disciplinary open access archive for the deposit and dissemination of sci- entific research documents, whether they are pub- lished or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.
L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Core protein domains involved in hepatitis C virus-like particle assembly and budding at the endoplasmic
reticulum membrane.
Christophe Hourioux, Malika Ait-Goughoulte, Romuald Patient, Delphine Fouquenet, Fabienne Arcanger-Doudet, Denys Brand, Annette Martin,
Philippe Roingeard
To cite this version:
Christophe Hourioux, Malika Ait-Goughoulte, Romuald Patient, Delphine Fouquenet, Fabienne Arcanger-Doudet, et al.. Core protein domains involved in hepatitis C virus-like particle assembly and budding at the endoplasmic reticulum membrane.: HCV core protein domain involved in viral morpho- genesis. Cellular Microbiology, Wiley, 2007, 9 (4), pp.1014-27. �10.1111/j.1462-5822.2006.00848.x�.
�inserm-00137282�
!#"$&%')(+*,-*.%/0* 213 546798!:8<;
=?>A@CBED#@F>6G0B?HJIK6>ML5N?HJI6OPHJIQ->ARSQB<KTHJIEU<B?DN<G.HVGWHXOY=2Q?HJ@WZ6O7[\RJHJ]BEDN?@FG^HV_RVB5N<OOB+L2`aRSb
N?I<KT`?Z<K6KAHJI-c2N<GdG.U-B5B?I<K#>+D6RVN6OLEHV_e@FBG^HV_ZaRJZ+L LfBaLE`?@FN?IB
g<hikjlnmkophqsr<otiujot,vwyxzd{|VjV}^{~ajmu#othot7|mkq,wyxo t{|s{,mFjq,m&wx<q7|VphjSqWottq7q,muwyx
W{jqq~aiyW{7qi&otq,muwyx<q,ldiy{wx~?q.m&mkqszd{iJmFjV,w{)h7jV|VjVp7pqojVq{iyxu
k^J ¡W¢¤£n¥V¦5§W¢J¨W\©«ªW£¬7¨W®^¡0¯¨W£°.¡²±Fª³n¢V£µ´·¶u¸¹^º,¬»¼º,¬¶)½^¾¿±Fª³n¢V£µ´§W¢J¨WÀµ¡Á¨W^°ÃÂ.¥V¦5°^¡ÅĦ\.¦Æ¥Çȳn¡
»?ª^¯¦^ÀC³\¯¨\¢É¡Ê°^¡F£YËu¢&³C£Ì¬7¡F£kÍ¢J¨^¥VªW¢J¡F£u´6Î.¸¬¹Ï¬.Ðѽ^¾ÒWÒµ´¶0£W¥V¥J³W¥7Ó^¨F£\¥Ç¡³n¢S´ÓW¨W¢J£u´§\¢J¨WÀµ¡
ÔÕ.Ö^Ö^×Ö0ØÙ&×ÙuÚÛÜ ÝÞ,ßàáâVÛäã^âSáWÙJÛ×ÖMå^áæ+ç.×Ö0è+×ÖFéWáÚé\ÛWå×ÖAé^×â¤ç,Ú^æ+áâJã.ê0á^Ø^Û,Ö0ÛWèF×è
ë ÞáâJâVÛWè0ãnáÖ0å,×Ö0ØEç,ÕFÙ&ênáâ&Üäì.ê^×Ú×ã.ã0ÛTÔ^á×ÖnØ^ÛWçâVå^íäîuïð^ñ,Ôòóñ,ÔîPôõäíökç,÷0áâVç0ÙJá,×âVÛøå^ÛEù×á,Úá^Ø,×Û2ÞÛÚÚÕ^Úç.×âVÛÆí
úFçWà0Õ^ÚÙJûÊå^Ûäò<ûWå^ÛWà0×ÖnÛÊå^Û+üáÕ^âVèCíônýä÷0áÕ.ÚÛFé\ç,âVåMüáÖ.Ö0Û,ÚÚû\í7ú0þJÿ^ý^ÿ?üáÕ^âSèaÞÛWå^ÛäúWâVçÖnàÛ
üÛ,Ú Jÿ^ÿÿWýô
úFçÿ^ÿdÿ.ýÊõ^ý
ñ^þæ+ç×Ú¤Ü7âVá,×Ö0Ø^ÛWç,âVåæ+ÛWåÕ^Ö^×éÆþÇÙÉáÕ^âVèyâ
t ) {iJ
r<qp{,mFjmFjlgjViktlFrg?Woiyq)piomkqjV,wq,vp7iyql0lWq! 9jmChs{"7q |SjV}j#uoiyq,lnm$jViktl%&'Miyqp|Çj0ow
lWq|(# {lnl\q Ï|q,l jV,mko r-g)-µ|VjV}^q¼p,{iJmFj^|ql*«r-g)-,+^l2{,m5mFhq q7op|{l^ Ïj iyq,mFj^t|Vt .-
sq iy{7q,wäpiojjVE{øopp,oiJmFtjmu5mkoølnmFtEr<g p,{iJmFj,|qø soiµpho7qq,ljl,øq|q0mFiyo
j,iyolWWop./{ikjotl t,mk{,mkqr-g)ÃWoiqepiomkqjVl0 )jmFhYqjÇqqiJqjV,mkqik{|q|q,mCjol1 ·qiq
q,vpiql\lWq2 9jmChsmFhjl lnlnm q wmkoejq,mFj(#y)Woiyq)7o s{jV,liqtjViyqoi6jl,pqlW{7|q3#&oi+r<g-,+^
{lWlWq 7|54hqr<gWoiJqPp7iyomkqjSlWqtq,\q3 {,lä0o p,{iyq )jmFhjmkl not,mkqikp{iJmÊjS)+jVikt,l
6µ+/- w<mChq7jViµtls sol0mÊ,|olnq|iq|{,mkqPmko5r<g/w<mko5j7q,mCj8#yÑWolWqi9qeo s{jV,l,+/-
{Ár<g jlp7|{, l,j jV|{imFiyop7jl\ #uoiE|Vj(,qiThqp,{,m o7nmkql {¼mFhqjVi20oiq piyom qjSl {iq
oi{j;:Wq²l,j jÇ|{iµ| jV,mko mFhiqq s{jS²o s{jV,l<,=µw>=?={@=?=?=? w{7|mFhoth A<k Woiyq jl
l^ s{|S|qia{7|{,}\lBA<CD{ jSoÑ{.jl3k{{jSYo s{jVE=n4h,qYq|q,mFjo9oF#al,hoiJmÊh,iyophoj
o s{jVlGµ{{IHCC?HD)JLKMH5D/CHNOPjVPr<gnoiyq:mh{,m+{pp,q{i+hjh|)0olWqi9qejV)o s{j¤L=?=
o#MomFh)?-CÑ{7er<gWoiqPpiyom q7jVliql^t|mkqejSP|olWldoF#Ìr<gWoiqL-{,h,oikjV{YlWq7|(#
{lWlWq 7|YjS,m oPr<g<,+^l,4hqsq|q,mFjooF#-l,hoi mao s{jÇl#uot3 )jmFh7jV7o s{7jV>=?oF#+r<ge0oiq
piomkqjV t,mÅomøjV mCh,q \oikiyq,l,poj¤ 7o s{jS oF#+/- Woiq {WnoiyjV mko lWqtqWq
HAL author manuscript inserm-00137282, version 1
HAL author manuscript
Cell microbiol 06/12/2006; epub ahead of print
HAL author manuscript inserm-00137282, version 1
HAL author manuscript
Cell Microbiol 2007;9(4):1014-1027
jlp,qlW{|q#yoiMr<g-,+.Ñ{,lWl0q Ï|Y{e soikp7ho7qql^jlnw )hqiyq{,l{{RR&HSN7 qiq iyqt7jViyq
#&oimFhjldp7iyoWql0l,4hqspiyo7tnmFjoäo#A<ksWoiyqspiomkqjV0#iyo {siyqWo )jS{m$&qnmkoi {l
{lWlWo^j{,m q )jmFh l,pq.j(#j - t|mFiy{lnmFiktnmCtiy{| ,h{7qlnw t,m j omÁ|q{ m o mFh,q
soiµpho7qql^jl5o5#9A-C T+,lnwäl^t7ql0mFjV mFh{,m)j8#P#&qiqmPtjDz qh{7jl\ sloW,ti)jV
sq qilÌoF#mFhq #u{ jS|
=n,mFiyotnmFjo
ÝÛ,ã0çnÙu×Ù&×èeÞ é^×âJÕ0èIuÝ7Þ,ß )×èeç5ènæ+ç^ÚÚMê0Û,ã0çnÙXáWÙuâVáã^×àé,×âJÕCè à0ÚçWèkèn×y×Û\åA×Ù&êW×ÖÙ&ênÛ
§W¯¨ J J¢J°^¨0¡
Xç,æÊ×ÚÖ
ÛWèkÙu׿+çnÙÛWå)ô&Wý^þuô.ýæÊ×ÚÚ×áÖäã0ÛWáã^ÚÛ#áâÉÚå+×å^Ûç,âVÛ×Ö?XÛWàµÙXÛWå+×Ùuê Ý7Þ,ß ?ÖnÛdáÙuê0Ûæ+ç Jáâ/XÛWç0ÙuÕ^âVÛWè+á#ÝÞ,ß
×Ö?XÛWàµÙ&×áÖ ×è:Ù&ê0çnÙ6æ+áâVÛÊÙuê0ç,Ö.ý"! á çWàWÕFÙJÛ,Ú×Ö?XÛWàµÙÛWåsã0çWÙu×Û,ÖFÙè÷0ÛWàáæ+Ûà0ê.âVáÖ^×àçÚÚ×Ö.XÛWàkÙJÛWå1#ÚÙÛ,â
¡^¥¨W¯
í
ôFõ^õ%,ÞÕ^âJâVÛ,ÖFÙåâJÕ0ØÙ&ê0Û,âVç,ã^×ÛWè+ç,âVÛdá VÙÛ,Öäã0áWáâJÚÊÙXáÚÛâVçnÙJÛ0ås÷$ã0çnÙu×Û,ÖFÙèAçÖnå ÛÉÛ\àµÙu×é\Û×ÖÊç,÷0áÕ«Ù&%\ý^þ'%%! á
àç\èÛWè ^î Ö+Ùuê0ÛÊç,÷0èÛÖnàÛÊá7Ù&âJÕ.ÚÛXÛWàµÙ&×éWÛÊà0Õ.âVç0Ù×é\ÛMÙuâVÛ\çnÙuæaÛ,ÖFÙJèFí,Ùuê0ÛWèÛÊànê^âVáÖ^×àM×Ö?ÉÛ\àµÙu×áÖnèaá VÙÛ,ÖÚÛ0çWåÊÙJáÚ×é\Û,â
àn×âJâJê0á^èn×èMç,Ö0åXçnÙJçÚênÛãnç0ÙJá^àÛ,ÚÚÕ^Úç,âàç,âVà0×Ö0áæaçGuúFÛ,Úå
¡^¥¨0¯
í^ý^ý(% ^üê0Ûé^×âVç,Ú^Ø^Û,Ö0áæ+ÛäàáÖFè0×èkÙJèMáçäõ(^þ')0÷
èn×Ö0ØÚÛ^þÉèuÙuâVçÖnå^ÛWå ã0á^èF×Ùu×éWÛ^þÉèÛ,Ö0èÛ Ôï* Û,Ö0àá^å×Önزç ã^âVÛWàFÕ.âVèáâPã0áÚ,ã^âVáWÙJÛ^×ÖTáYç,÷0áÕ«Ù ÿWý^ý^ý ç,æM×Ö0áþÉçWà0×å
âVÛWè0×åÕ0ÛWè&7ì0á,Úã^âVáWÙJÛ^×ÖMÙuâVç,Ö0èFÚçnÙ&×áÖä×èM×Ö^×Ùy×çnÙJÛ\åé^×ç÷\×Önå×Ö0Ødá -âJ×÷ná^èkáæ+ÛWè#Ùáäç,Öd×Ö«ÙÛ,âJÖ0ç,Ú,âJ×÷Cá.èkáæ+ÛdÛ,ÖFÙuâ+Êè0×ÙJÛ
yî Ôñ^ðJíÚá.àçnÙJÛ\å,?×Ù&ê.×Ö+Ùuê0Û%.-.Õ^ÖFÙuâVç,Ö0è0ÚçnÙJÛWåâVÛWØ,×áÖ /%.-0^üÔ%*1Õ^âJ×Ö0ØÙ&âVç,Ö0ènÚçnÙy×áÖ\íÙ&ê0Ûäæ+çnÙuÕ^âVÛMé×âSç,Ú^ã^âVá^åÕ0àkÙJè
ç,âVÛØ^Û,Ö0Û,âVçnÙÛWå!yâVáæEÙuê0Û)ã0á,Ú,ã^âVáWÙJÛ^×Ös÷$ çäèÛâJ×ÛnèÊá<àFÚÛWçFé\çWØ^ÛÛ0éWÛ,ÖFÙèuöF×Önå^Û,Ö^÷0çWà0êäç,Ö0åÔ×àÛÆí ^ý^ý2% %.üê0Û
èµÙ&âJÕ0àµÙuÕ^âVç,Ú\àáæÊã0áÖnÛÖ«Ùè43ÉáÖ0ÛàáâVÛJÞç,Ö0åÙ56áäÛ,ÖFé\Û.Úáã0ÛuñôMç,Ö0åsñ #ã.â¤áWÙJÛ,×Ö0è6ç,âVÛã.âVá^åÕ0àÛWå÷7dàÛ,ÚÚÕ^Úç,â
ã^âVáWÙJÛWçWèÛ^þæ+ÛWå×ç0ÙJÛWåànÚÛ\çnéWç\Ø.Û0èì^âVá^àÛWèkè0×ÖnØáÙuê0ÛsÖ0áÖ\þÉèµÙuâJÕ0àkÙuÕ^âVç,Úã^âVáWÙJÛ,×Ö0èuïð.þïð%^ù-Ù&ê0çnÙ<ç,âVÛ×Ö«é\áÚéWÛ\å
×Öã0áÚã^âSáWÙJÛ×Öã^âVá^àÛ\èµè0×Ö0ØçÖnåäé×âSç,ÚÔïeâVÛ,ãWÚ×àçnÙy×áÖâVÛ98Õ.×âVÛ\èAé×âJÕFèFþÉÛ,Ö0àá.å^ÛWå)ã^âVáWÙJÛWç\èÛ0èuöáê^æ+ç,Ö^Ö
¡^¥¨W¯
í
ôFõ^õ5%,üê0ÛÖCáÖ0èkÙuâJÕ0àµÙ&Õ.âVçÚã^âVáÆÙXÛ,×Ö0èÊç,âVÛèÛ,ã0ç,â¤çnÙJÛ\å3âVáæTÙuê0ÛsèkÙuâJÕ0àµÙ&Õ^âVç,Úã^âVáWÙJÛ^×Önè÷$çsè0êFáâSÙMê$\åâVáã^ê0á÷W×à
ã0áÚ,ã0Û,ãFÙy×å^Û ã í,Ùuê0Û yÕ^Ö0àµÙu×áÖÌá:+ê^×ànêd×èMÕ^Ö)nÖ0á+Ö5
üê0ÛÝÞ,ßeàáâ¤Ûã^âVáWÙJÛ^×Ös×èã.â¤á^åÕ0àÛWå)çnÙ6Ùuê0Û)ïþÇÙÛ,âJæÊ×Ö0ç.ÚÛ.Ö0å)á<Ùuê0Ûã0á,Úã^âVáWÙÉÛ×Öç,Ö0å×è XáÚÚá#Û\å÷$
Ùuê0Û)è0רÖ0ç,ÚèÛ98Õ0Û,Ö0àÛ)á6Ùuê0ÛPñôÛ,ÖFéWÛ^Úáã0Û)Ø,ÚWàáã.â¤áWÙJÛ,×Öüê0Û)ènרÖ0ç.ÚèÛ98ÕnÛÖnàÛsÙJç,âVØ^ÛnÙXèÙ&ê0ÛPÖnç\èàÛÖ«ÙÝ7Þ,ß
ã0áÚ,ã^âVáWÙXÛ,×ÖäÙJáÙuê0ÛsÛ,Ö0å^áã^Úçnè0æÊ×àâVÛnÙy×à0Õ.ÚÕ^æQuñ,Ô Jíç^ÚÚá9A×ÖCØsÙuê0ÛÙ&âVç,Ö0ènÚá^àçnÙy×áÖá?ñôÙÉásÙ&ê0Ûñ^ÔeÚÕ.æ+ÛÖWíçÖ
ÛWèèÛ,ÖFÙu×ç^ÚWèkÙJÛ,ã×ÖÊÙuê0Ûsæ+ÛæÊ÷.â¤ç,Ö0Û^þÉå^Û,ã0Û,Ö0å^Û,ÖFÙ?ã^âVá^àÛWèè«×Ö0ØäáÙuê0ÛäàáâVÛsã^âVáÆÙÛ.×Ö uöF×Õ
¡^¥¨0¯
íôFõ.õ %Þ7ÚÛWç0éWçWØ^Û
÷$dçè0רÖnçÚ,ã0Û,ãFÙu×å^çWèkÛ×ÖMÙuê0Ûñ,Ô)ÚÕ^æ+Û,ÖäâVÛ,ÚÛ\çWèÛWè?Ù&ênÛïþÇÙJÛ,âJæÊ×Ö0ç,Ú\Û,Ö0åäá<ñô0íÚÛ\çné^×Ö0ØÙuê0Ûô«õô0þÉç,æÊ×Ö0áäçWà0×åWè
JçWç#àáâVÛ)ã^âSáWÙÛ,×Öäç,Ö0à0ênáâVÛWå)÷$äÙ&ênÛ ènרÖ0ç.Úã0Û,ãFÙu×å^ÛGuò<ànökç,Õ0à0ê.ÚçÖ
¡^¥¨W¯
í ^ý^ý .üê^×è ô«õônþÉç\çÏã0á,Úã0Û,ãFÙy×å.ÛÆí
ç,Úèá;)0ÖFá+Ö2ç\è2ã ^ÿ.í×èç,ÖT×æÊæ+çnÙ&Õ.âVÛ ÉáâJæÁáÙuê0ÛEàáâVÛ ã.âVáWÙÛ,×Ö\í·çÖnå²×è yÕ^âSÙuê0Û,â)ã^âVá^àÛWèèÛWå²÷$EçÖ
×ÖFÙuâVç,æ+ÛæÊ÷.âVçÖnÛã^âVáWÙJÛWçWèÛWíÙuê0Ûè0רÖnçÚ,ã0Û,ãFÙu×å^ÛãnÛã«Ùy×å^çWèÛð,ì^ì íÙ&ê0çnÙànÚÛWçné\ÛWè+×Ùuê^×ÖMÙuê0ÛdÞþÇÙJÛ,âJæÊ×Ö0ç,Ú\èFרÖ0ç,Ú
ã0Û,ãFÙu×å^ÛsçÖnåPâVÛ^ÚÛWçWèÛnèÊÙuê0ÛYïþÇÙÛ,âJæM×Ö0ç,Úô&^ÿ.þyô&ÆõçWçsá<Ù&êFÛsàáâVÛYã^âVáÆÙÛ.×ÖyâVáæ Ù&ênÛ)ñÔL ò-ànöç,Õ0ànê^Úç,Ö
¡^¥<¨n¯
í
^ý^ý%<üê^×èPà0ÚÛWç«é\ÛWåøàáâVÛEã^âVáWÙÉÛ×ÖWíÊç^Úèµá<)0Öná+Öç0èã ,ô0íä×èÙ&ênÛÖçné\ç,×Úç,÷^ÚÛ Xáâç\èµèá^àn×ç0Ùu×áÖ=?×Ù&ê2Ú×ã^×å
åâVáã.ÚÛ0ÙJè uò<ànöç,Õ0ànê^Úç,Ö
¡^¥7¨\¯
í/^ý^ý áâæ+áâJã^êná^Ø^Û,Ö0ÛWè0×è?áÙuê0ÛMé×âVç,Ú^ã0ç,âSÙu×à0ÚÛ#×Ùyþ?>áÕnØê0áÕ^ÚÙJÛ
¡^¥7¨\¯
í/^ýWý%
üê^Õ0èFíã ô×è?Ù&ênÛæ+çnÙ&Õ.âVÛXáâJæEáÙuê0ÛdàáâVÛã.âVáWÙÛ,×Ö XáÕ.Ö\ås×ÖMÙ&ênÛdèÛ\ànâVÛnÙÛWåé×âVç,Ú,ã0ç,âSÙ&×ànÚÛ\í7çWè+ènê0áAÖ ÷7ÊÙ&ê0Û
ã^âVÛWå^áæÊ×ÖnçÖnàÛáÊã.ô)×Ö)èÛ,âJÕ^æ áÊã0çnÙy×Û,ÖFÙès×Ö?ÉÛ\àµÙJÛ\å@?×ÙuêPÝÞ,ß #Açnè0Õ.×
¡^¥?¨0¯
íAôFõWõTüê0ÛPâVá,ÚÛYá aàáâVÛ
çWèèá^àF×çnÙu×áÖ+×ÙuêÚ×ã^×ååâSáã^ÚÛnÙXè×ÖÊÙuê0Ûé×âSçÚ,Ú×XÛäàB\ànÚÛâVÛ,æ?ç,×Ö0èdêná6Ûné\Û,âÚç,âVØ^Û^ÚsÕ^Ö)0Öná+ÖWüê^âVÛWÛäå^áæ+ç.×Ö0è
ê0çné\ÛÏ÷0ÛWÛÖs×å^Û,ÖFÙy××Û\åÏ×ÖÝÞ,ßPàkáâVÛ)ã.âVáWÙÛ.×Ö\í÷0çWèÛWåáÖsã^â¤ÛWå×àµÙJÛ\åsèµÙ&âJÕ0àµÙuÕ^âVç,Ú^çÖnåGyÕ.Ö0àkÙu×áÖ0ç,Ú^ànê0ç,âVçWàkÙJÛ,âJ×èkÙy×àè
uÝ7áã0Ûäç,Ö0å)ò<à0öç,Õ0à0ê.ÚçÖWí^ý^ý^ý :1áæ+ç,×Ö îJíàáâJâVÛWènãCáÖ0å×ÖFØäÙJáäÙ&ênÛïþÇÙÛ,âJæÊ×Ö0ç,Ú^ç,ã^ã^âVá׿+ç«ÙÛ,Ú)ô .ýäçWç\í×èMç
HAL author manuscript inserm-00137282, version 1HAL author manuscript inserm-00137282, version 1
æ+áâJã^êná^Ø^Û,Ö0ÛWè0×è 17áæ+ç^×ÖdîyîJíÚá^àçnÙÛWås÷0ÛnÙ#Û\Û,ÖÊçWç#ô .ýÊç,Ö0åäçWç6ô%0í×è+çê$\åâVáã^ê0á÷^×àâVÛ\Ø,×áÖäã^âVÛWå×àµÙJÛ\å
ÙJá XáâJæ áÖ0Û5áâÊÙ5<á
αþê0Û,Ú×àÛWèÙuê0çnÙ·ç,âVÛEã^âSá÷0ç,÷^ÚE×ÖFé0áÚé\ÛWåE×Ö Ù&ê0Û5çWèèká^àn×çnÙy×áÖá àáâVÛ +×Ù&ê Ù&ênÛEñÔ æ+Û,æÊ÷^âVç,Ö0Ûäç,Ö0å)Ú×ãW×ååâVáãWÚÛnÙJè&:1áæ+ç.×Ö îJîyîJí àáâJâVÛWènãFáÖ0å×Ö0ØäÙJáäÙuê0ÛäÞþÇÙÛ,âJæÊ×Ö0ç.Ú^ýäç0çäáÙ&ê0Ûsã^âSáWÙJÛ,×Ö«í-×èMç
ê^רê.Úê$\åâVáã^ê0á÷^×àâVÛ\Ø×áÖMÙ&ê0çnÙèÛ,âSé\Ûnè+çWè+çdènרÖ0ç,ÚWèÛ98ÕFÛ,Ö0àÛXáâ7Ùuê0ÛÙç,âVØ^ÛnÙu×Ö0Øäá<ñôAÙJádÙuê0ÛñÔ"èÛWÛúWר
ô&T
Ô,Û\àÛ,ÖFÙ6çWåWé\ç,Ö0àÛWèd×ÖÙuê0Ûå^Ûné\Û.Úáã^æ+Û,ÖFÙ<á<àÛ,ÚÚànÕ^ÚÙ&Õ.âVÛ èB0èµÙÛ,æ+èäê0çné0Û)æ+çWå^Ûs×Ù+ãFá^èèF×÷^ÚÛ0XáâÙ&ê0Û1×âVèµÙ
Ùu׿+ÛsÙáPã^âVá.åÕ0àÛP×Ö?XÛWàkÙu×áÕ0èsÝÞ,ßeÙuê0çnÙaàç,ÖY÷0Û)Ûy×àn×Û,ÖFÙuÚYã.âVáã0çWØ^çnÙÛWåP×Ösà0Õ^ÚÙuÕ^âVÛWåí:Ö0çéWÛPê0Û,ã0çnÙXáæ+ç)àÛÚÚè
uön×Ö0å^Û,Ö^÷0çWànê
¡Æ¥:¨\¯
í ^ýWý% ç)0×ÙXç
¡Æ¥:¨\¯
í ^ý^ý%ê0áÖ0Ø
¡^¥?¨W¯
í ^ý^ý2% %7üê0ÛWèÛ Ö0Û9 èB\èµÙJÛæ?è ?×ÚÚànÚÛWç,âJÚ
ã^âVáWé,×å^ÛãFá#Û,âyÕ^ÚnÙXá^á,Úè Xáâ7çÖnçÚn×Ö0ØsêFá^èµÙàÛ.ÚÚþÇé^×âJÕ0èM×ÖFÙJÛ^âVçWàkÙu×áÖ0èFí÷.ÕFÙ6×Ù<âVÛ,æ+ç×ÖFèÊÖnáWÙ6ãFá^èkèn×÷WÚÛÊÙJáÊé×ènÕ0ç,Ú×Û
ÝÞ,ß5çWèèÛ,æÊ÷\ÚYç,Ö0åæ?áâJã^ê0á.Ø^Û,Ö0ÛWèF×è+×ÙuêÙuê0ÛWèkÛ æ+á^å^Û^ÚèG ÔáÕ^×ÚÚû
¡^¥?¨W¯
í$^ý^ýTÛ ê0çné\Û)ÛWèµÙç,÷WÚ×ènê0ÛWåPç
æ+á^å^Û,Ú÷0çnèÛWåsáÖðWÛ,æÊÚ×)n×XáâVÛ\èµÙ<é^×âJÕ0èyð,úß AâVÛ,ã^Ú×àáÖäéWÛ0àµÙáâVèFí +êW×ànêàç,Ö)÷0ÛÕ0èÛWåÙJáYã.âVá^åÕ0àÛYÝ7Þ,ß àáâSÛ
ã^âVáWÙJÛ,×Ö×Ösæ+ç,æÊæ+ç,Ú×çÖäàÛÚÚèFí<ÚÛWç\å×Ö0ØÙJáÙ&ê0Ûç\èèÛæÊ÷.ÚáÙuê^×èäã^âVáÆÙÛ,×Ös×ÖFÙáÝÞ,ßþÚ×)Û)ã0ç,âSÙ&×à«ÚÛ\è ÝÞ,ßþö0ìnè
uùÚç,Ö0ànê0ç,âVå
¡^¥6¨W¯
í$.ý^ý+ùÚç,Ö0ànê0ç,âVå
¡^¥#¨W¯´
^ý^ý.ÿ Tüê^×èsæ+á^å^Û,Úå×ènã^Úç 0èç,÷CáâSÙ&×é\Û ÝÞ,ßþö0ì÷^Õ0å^å×ÖnØíA÷^ÕFÙ
âVÛ,æ+ç,×Ö0èçeÕnèÛyÕ^ÚÙá^á,Ú/Xáâ?Û^ÚÛWàµÙ&âVáÖPæÊ×ànâ¤á.èàáã$Luñ,ò$+èµÙyÕ0å×ÛWèá aÙuê0ÛÛ\ç,âÉÚYÛné\Û,ÖFÙXèá Ý7Þ,ßÃçnèèÛ,æÊ÷\ÚP×Ö
æ+ç,æÊæ+ç,Ú×çÖMàÛ,ÚÚè ?×Ù þ?>áÕ0Øê0áÕ.ÚÙÛ
¡^¥7¨0¯
í.ý^ýÔá,×Ö0Ø.Û\ç,âSå
¡^¥7¨W¯
íWý^ý5 îuÖAÙ&ê.×èaè Ù&Õ0å Æí#ÛäÕ0èÛ\åÙ&ê.×èMÝÞ,ß
àáâVÛäç\èèÛæÊ÷WÚsæaá^å.ÛÚÉáâÙuê0Ûsã^âVá^åÕ0àkÙu×áÖÊáèÛné\Û,âSçÚ^å.Û^ÚÛ0Ùu×áÖæÊÕ«Ùç,ÖFÙJè+áÙuê0ÛsÝÞ,ßYàáâVÛsã^âVánÙÛ,×Ö\í×ÖdáâVå^Û,â
ÙJáY×å^Û,ÖFÙ×å^áæ+ç^×ÖnèÌáÙuê0ÛàáâVÛsã^âVáWÙJÛ^×ÖÙ&ê0çnÙ6ç,âVÛsâVÛ98Õ^×âSÛ\åsáâå×ènã0Û,Ö0èç,÷\ÚÛ1Xáâé×âJÕFèäæ+áâJã.ê0á^Ø^Û,Ö0Ûnè0×è Û
×å^Û,ÖFÙu×y×ÛWå èÛ98Õ0Û,Ö0àÛWè5áÑãnáWÙÛ,ÖFÙu×ç^Ú×ÖFÙJÛâVÛWèµÙe÷$TàáæÊã0ç^âJ×Ö0Ø Ùuê0ÛTàáâVÛ²ã^âVáWÙJÛ,×ÖÅèÛ98Õ0Û,Ö0àÛTáPÝÞ,ß kôFç
Ø^Û,Ö0áWÙ?ãnÛ A×Ù&êMÙuê0çnÙá ><ùé^×âJÕ0èÊùG?><ùWßþùyíÙ&ênÛÊé×âJÕnèÊæaá.èkÙànÚáWèÛ,ÚâVÛ,Úç0ÙJÛWåÙXásÝÞ,ß2 úWרô&T7ù\áWÙuê4><ùWßþù
ç,Ö0åeÝ7Þ,ßå×ènã^Úç ÙuâVáãW×è0æUXáâ+Ú×é\Û,â+ê0Û,ã0çnÙJá^àB0ÙJÛ\èí<ç,Ö0å > ùWßþù 6çWè0y×âSèkÙÊ×èkáÚçnÙJÛWåe×ÖÙJç,æ+ç,âX×Ö0èäçVÙJÛ,â6èÛ,âJ×ç.Ú
ã0çWèèçWØ^ÛnèÌáèÛ,âJÕ^æ yâVáæÅçäènÕ^âVØ^ÛWáÖ?×ÙuêÖ0áÖ7þÖ0áÖ^ù)ê0Û.ã0çnÙ&×Ùu×è >ùWßþùs×èÊ×Ö?XÛWàµÙ&×áÕ0èÊ×ÖÊÙJç,æ+çâÉ×Ö0èMç,Ö0å)ê0çWè
÷0ÛWÛ,Ödã^âVáã0á^èÛ\åçWèaçÊènÕ^âJâVá^Ø.ç0ÙJÛäæ+á^å^Û,Ú?ÉáâÝÞ,ß> ù^ÛWçæ+ÛWè
¡Æ¥7¨W¯
í/^ý^ýWýù^ÛWç,æ+Û0è
¡^¥7¨\¯
íWý^ýôò-ç,âSÙu×Ö
¡^¥7¨W¯
í
^ý^ý.ÿ%><ùWßþ ù9ç,Ö0åPÝ7Þ,ß àáâVÛã^âVáWÙJÛ,×ÖèkÛ98Õ0Û,Ö0àÛ\èå×ènã\Úç7ènרÖ^×J×àç,ÖFÙ?è0׿M×Úç,âX×Ùu×Û0èFí ×Ö)ã0ç,âSÙ&×ànÕ^Úç,âÙ&ê0Û Y÷náWÙ&ê
àáÖFÙJç×Ö2çÅå.áæ+ç,×Ö<Jå^áæ+ç×ÖEîJîPsÙuê0çnÙP×èç,÷0èÛ,ÖFÙ"âVáæóÙuê0ÛEàáâVÛ ã^âVáWÙJÛ×ÖnèásáWÙ&ênÛâ)æ+Û,æÊ÷0Û,âVèáÙuê0Û
§W¯¨ JJ y¢É°^¨W¡
ÉçæÊ×Ú1 ù\áÕ^Úç,ÖFÙ
¡^¥¨W¯
í ^ý^ý2%<ÝáãnÛ
¡^¥¨W¯
í \ý.ý%Wüê0ÛäàáâVÛsæÊÕFÙJçÖ«ÙèMÛ,Ö0Ø×Ö0ÛWÛ,âVÛWåç,ÚÚá#ÛWå)Õ0è
ÙJáY×å^Û,ÖFÙu×èÛ.8Õ0Û,Ö0àÛWè×Ö å.áæ+ç,×Ö·îJîíçWè46Û.ÚÚçnèÊçè0ênáâSÙ-èÛ98Õ0Û,Ö0àÛ)×Öäå^áæ+ç,×Ö·î#áÙuê0Û)ÝÞ,ßPàáâVÛÏã^âVáWÙJÛ×Ö
Ùuê0çnÙ-ç,âVÛsÚ×)Û,ÚâVÛ98Õ.×âVÛ\å1Xáâ<ÝÞ,ße÷^Õnå^å×Ö0Ø7îuÖdçWå^å×Ùu×áÖ\íÙyê0ÛäàáæÊã0ç,âJ×èáÖá ><ùWßþùç,Ö0å)Ý7Þ,ßYàáâVÛsã^âVáÆÙÛ,×Ö
Ûã^âVÛWèèF×áÖ3yâVáæ ð,úµßéWÛ\àµÙJáâ¤èè0Õ0Ø.Ø^Û0èµÙè·Ù&ê0çnÙÌå,×ÉÛâVÛ,ÖFÙÊ÷^Õnå^å×Ö0Øæ+ÛWà0ênçÖ.×è0æ+èäá^àà0Õ.âÌ×ÖPæ+Û,æÊ÷0Û,âVèäá?Ù&ê0Û
§W¯¨ JJ y¢É°^¨W¡
Xç,æÊ×Ú
q,l,t|m&l
º0Í¢J¡F£k£nª.dª-Î<Ë?Àµª^¢J¡?Í¢Jª¥Ç¡00£µ´<Î<Ë?Àkª.¢J¡Ê°^¡0¯¡^¥Sª^ ³W¥Ç¨\,¥£µ´¨W^°ÄaËsÀkª^¢J¡?Í7¢Jª¥V¡n
ðWÛné\Û,âVç,Ú^ã^ÚçWènæÌ×å.èaÛ,Ö0àá^å×ÖnØÝÞ,ßàáâVÛäæÊÕFÙJç,ÖFÙJè6Ùuê0çnÙàáÖFÙç,×ÖÕ^Ö^×8Õ0ÛÊáâàáæÊ÷^×Ö0ÛWådå^Û,ÚÛnÙu×áÖ0è?áÙuê^âVÛWÛÊènê0áâSÙ
èÛ.8Õ0Û,Ö0àÛWèã^âVÛWèÛ,ÖFÙ+×ÖäÙuê0Ûså^áæ+ç^×Öî#á+Ý7Þ,ß àáâVÛ)÷.ÕFÙÌÖ0áÆÙÌ×ÖäÙuê0ÛàµáâJâVÛWè0ã0áÖ0å,×Ö0Ø)å^áæ+ç.×Öá&>ùWßþù9àáâSÛ
Jå.ÛÚ,ô0íçÖnå ÿíáâå.ÛÚÛnÙu×áÖÌá Û,×Ù&ênÛâ7áâ÷0áWÙuêÌá Ù56ádènêWáâSÙ<âVÛÚçnÙu×é\Û.ÚàáÖ0èÛ,âSé\ÛWådèÛ98Õ0Û,Ö0àÛ\èM×ÖMå^áæ+ç,×ÖîJî
áäÙuê0ÛøàáâVÛTã.âVáWÙÛ,×Öá)÷0áWÙuêé^×âJÕnèÛWèIå^Û^Ú EçÖnå<% 6Û,âVÛøØ.ÛÖnÛâVçnÙJÛWå úWר äô&TÌð,×0ÙJÛWÛ,ÖÅênáÕ^âVèeçVÙJÛ,â
ÙuâVçÖnè%XÛWàµÙ&×áÖ<+×ÙuêEÙ&ê0Û²ð,úß¼âVÛWàáæÊ÷.×Ö0ç,ÖFÙÑàáÖ0èµÙ&âJÕnàkÙJèEÛ&,ã^âVÛWèè«×Ö0زÛWç\ànêTá)Ùuê0ÛWèÛ ÝÞ,ß àáâVÛ å^Û,ÚÛnÙ&×áÖ
HAL author manuscript inserm-00137282, version 1HAL author manuscript inserm-00137282, version 1
6ÛWèµÙÛ,âJÖs÷^ÚánÙ6ç,Ö0ç,Ú0è0×è 7Þ,áÖ0èn×èµÙÛ,ÖFÙ&A×Ù&êáÕ^â6ã.âVÛ0é,×áÕ0èäâVÛ0èFÕ.ÚÙè#×Ùþ>áÕ0Øê0áÕ^ÚÙJÛ
¡^¥¨W¯
í\ý.ý<ù,ÚçÖnà0ê0ç,âVå
¡^¥
¨W¯´
^ý.ý\ÿyí Ù&âSç,Ö0è%ÉÛ\àµÙu×áÖdáÙ&ênÛ +×ÚåþÇÙ?ã0Û"Êü#ÞôFõôàá,Ö0èµÙ&âJÕnàkÙ+×ÖsùÝþ ôâVÛnè0Õ.ÚÙÛWå)×ÖÙ&ênÛ)ã^âVá^åÕnàkÙu×áÖ á
ê^רênÛâç,æ+áÕ^ÖFÙJèÊá<àáâVÛÏã^â¤áÆÙÛ,×ÖÙ&ê0ç,Öäå,×åÙuê0ÛäÙuâVç,Ö0è%ÉÛ\àµÙu×áÖäáÙ&ênÛÞô&^ÿàkáÖ0èµÙuâJÕ0àkÙ úWר íÚç,Ö0ÛWèäôdç,Ö0å
ÿTÚèá)àkáÖ0èn×èkÙJÛ,ÖFÙ A×Ù&êäáÕ^â?ã^âVÛné×áÕ0è,<áâ5) #×Ùyþ?>áÕ0ØêCáÕ^ÚÙÛ
¡^¥<¨n¯
í'.ý\ý6ùÚç,Ö0ànê0ç,âVå
¡^¥<¨0¯´
^ýWý^ÿyí Ù&ê0Û
düÞôõôMàáâVÛã^âSáWÙÛ,×Ö46çnè yÕ^ÚÚdànÚÛ\çné0ÛWås÷$ ð,ì^ìWíÙuê0ÛàFÚÛ0çné\ÛWå ÊüYÞô«õô+àáæÊרâVçnÙy×Ö0ØA×Ù&êMÙuê0ÛdÞô?^ÿàáâVÛ
ã^âVáWÙJÛ,×ÖÊç\èAç ô,)17çã^âVá^åÕ0àkÙ'uúWר .íÚç,Ö0ÛnèdôMç,Ö0åÿ%*1×XÛ,âVÛ,Ö0àÛ\è×ÖÌÙuê0Ûçæ+áÕ^ÖFÙJè+áÙ&ênÛ düÞôFõôMç,Ö0å
Þô&^ÿàáâVÛäã^âVáWÙJÛ×ÖnèÌã.âVá÷0ç,÷WÚ âVÛWènÕ^ÚÙÛWåyâVáæøçäÚçWà )aá7Ùç,âVØ^ÛnÙu×Ö0Ødá Þô&^ÿÙáÙ&ênÛäñÔsæ+Û,æÊ÷^âVç,Ö0Û^íÚÛWçWå×Ö0ØÊÙJá
çÊå^ÛXÛWàµÙ-×Öæ+Û,æÊ÷^âVç,Ö0Ûdç,Ö0ànê0áâJ×Ö0Øç,Ö0åsã0áWÙJÛÖ«Ù&×ç,ÚÚäê^רê0Û,âÚÛné\Û,Úè?áå^ÛWØâVçWå^çnÙu×áÖÌåÕ0ÛMÙJáÕ.÷^×8Õ^×Ùu×Ö0çnÙ&×áÖÌç,Ö0å
ÙJçâVØ.Û0Ùu×Ö0ØÙáÙ&ê0Ûäã.âVáWÙÛWçWèáæ+Ûyð,Õ0Õ)n×
¡^¥7¨\¯
í/^ýWýô&%FüênÛäÝÞ,ßàáâVÛäæÊÕFÙJçÖ«ÙèMã^âVá^åÕ0àÛWåyâVáæ5Ùkê0ÛÊå.ÛÚ,ô0íå^Û,Ú
^íå^Û,Ú\ÿ^íå.Û^Ú%MçÖnådå^Û,Úô%ÊàáÖ0èµÙ&âJÕnàkÙJèMê0çWådènÚרê«Ù&ÚdÚá26Û,âçã.ã0ç,âVÛÖ«Ù-æ+áÚÛ\ànÕ^Úç,â #ÛרêFÙè#Ùuê0ç,Ö+Ùuê0Û dü)Þôõô
àáâVÛYã.âVáWÙÛ,×Ö\í Aê^×ànê)×èdàáÖFè0×èµÙXÛ,ÖFÙ A×Ù&êäÙuê0Ûså^Û,ÚÛnÙ&×áÖ0è×ÖÙuâVá^åÕnàÛWåLuúWר. %ÝÞ,ßeàáâVÛå.ÛÚÛnÙ&×áÖ)æÊÕFÙç,ÖFÙJè
Ûã^âVÛWèèÛWåâ¤áæEÙuê0Ûäå^Û,Úç,Ö0åå^Û,ÚÿàáÖ0èkÙuâJÕ0àµÙè 6Û,âVÛsã^âSá^åÕ0àÛWå)×Ödèn׿Ì×Úç,â 8ÕnçÖ«Ùy×Ù&×ÛnèÌçWèAÙ&ênÛ dü ã^âVáWÙJÛ^×Ö\í
+ênÛâVÛWçWèÙ&êná^èÛ5Û,ã^âVÛ0èèÛWå yâVáæ¼Ùuê0Û5å^Û,ÚÌô0íå^Û^Ú %áâÊå^Û,ÚÌô%5àáÖ0èµÙ&âJÕnàkÙJè@6Û,âVÛEã^âVá^åÕnàÛWåT×Öè0æ+ç.ÚÚÛ,â
ç,æ+áÕ^ÖFÙJèFíç0èdàáÖ?×âJæ+Û\å×Ö)âVÛ,ã0ÛWçnÙXÛWå)Û&,ã0Û,âX׿+Û,ÖFÙJèüêW×èäæÊרêFÙM÷0ÛsåÕ0ÛÙXáPê^רê0Û,â#×Ö0èkÙJç,÷W×Ú×Ù?áÙ&ênÛYÚçnÙÉÙXÛ,â
èÛâJ×ÛWèÊá6å.Û^ÚÛnÙy×áÖ)æÊÕFÙJç,ÖFÙÌã.â¤áWÙJÛ,×ÖFè öá#Û,â6æ+á,ÚÛWà0Õ^Úç,â <Û,רêFÙMã^âVá^åÕ0àµÙJèíàáâJâVÛ^ÚçnÙÛWåsÙXásÙuê0Û)ã.âVá^åÕ0àµÙ&×áÖ á
Úç,âVØ^Ûç,æ+áÕ^Ö«ÙèMá?ã^âVÛWå^áæÊ×Ö0ç,ÖFÙ+ã^âVá.åÕ0àµÙè4#ÛâVÛäá÷nèÛ,âSé\ÛnåY×Öäèáæ+Ûàç\èÛ0è ú0ר í<Úç,Ö0ÛWèäô0í %«íçÖnå
üê0ÛWèÛYæM×Ö0áâç\å.å×Ùy×áÖ0ç,Ú7ã^âVá^åÕ0àµÙJèäæÊרêFÙÌâVÛ,ã^âVÛnèÛ,ÖFÙ?å^ÛWØâSç\å.ç0Ùu×áÖ)ã^âSá^åÕnàkÙJèCíçWè46Ûã^âVÛné^×áÕ0èFÚ)âVÛ,ã0áâSÙJÛWåY×Ö
Ùuê^×èdæ+á.å^Û^Ú ùÚç,Ö0ànê0ç,âVå
¡^¥¨W¯
í^ý.ý^ÿ ^üê0ÛsÝÞ,ßYàáâVÛsæÊÕFÙXç,ÖFÙ<Û,Ö0àá^å^ÛWå)÷$Ù&ê0Ûäå^Û,ÚàáÖ0èµÙuâJÕ0àkÙ 6çWè÷0ç,âVÛ^Ú
å^ÛnÙJÛ\àµÙJÛ\å3uúWר íÚç,Ö0ÛGíç,Ö0åäÙuê0ÛsÝÞ,ßYàáâVÛæÊÕ«Ùç,ÖFÙ<ÛÖ0àá^å^ÛWå)÷$Ù&ênÛ å.ÛÚ%dàáÖ0èµÙ&âJÕnàkÙ$uÚç,Ö0Û)ô0ý 6çWè
å^ÛnÙJÛ\àµÙJÛ\åPáÖ.ÚYç&ÇÙÛ,âMã^âVá,ÚáÖ0Ø^ÛWåPÛ?,ã0á^ènÕ^âVÛ)á?Ù&ênÛy×Úæ Éå^çnÙç Ö0áWÙÌènê0áAÖ %7üê^×è 6çWèsÖ0áWÙdÚ×Ö)Û\åÙJá@6Û0ç)
å^ÛnÙJÛ\àµÙu×áÖøáå.ÛÚ çÖnåTå^Û,Ú %2àáâVÛEå^Û,ÚÛ«Ù&×áÖ æÊÕFÙç.ÖFÙJèø÷$2Ù&ênÛÅÞô % Eç,ÖFÙu×þÝÞ,ß àáâVÛ æ+áÖ0á^ànÚáÖ0ç,Ú
ç,ÖFÙu×÷0á^å9^íç0è#éWçâJ×áÕCèMæ+áÖná^à0ÚáÖ0ç^Ú0ç,Ö0åã0áÚWà0ÚáÖnç^Ú0ç,ÖFÙu×þÝÞ.ßàáâVÛÊçÖ«Ù&×÷0á.å×ÛWèaØ.ç0éWÛÊèF׿Ê×ÚçââVÛ\ènÕ^ÚÙXè å^çnÙçäÖ0áÆÙ
ènê0á+Ö% ÛYá÷0èÛ,âé\ÛWåæ+ç,â5)ÛWåPàÛ,ÚÚå^ÛWç0ÙuêP×Ö)à0Õ^ÚÙuÕ^âVÛWèäÙyâVç,Ö0èTXÛWàµÙÛWå@+×Ùuê)å^Û,Ú Pç,Ö0åPå^Û,Ú %)àáÖ0èkÙuâJÕ0àµÙèFí
ènÕ0Ø^Ø^ÛWèµÙ&×Ö0Ø Ù&ê0çnÙMÙ&ênÛÑÛ,ã^âVÛWèkè0×áÖYá+Ùuê0ÛWèÛPàáâVÛPå^Û^ÚÛnÙu×á,ÖeæÊÕ«Ùç,ÖFÙJè #çWèÙJá×àÙJáeàÛ.ÚÚè&üê0Û@>ùWßþùeàáâVÛ
ã^âVáWÙJÛ,×Ö 6ç0èÏã^âVá^åÕ0àÛWåPÛ&y×à0×Û,ÖFÙuÚYç\èäç ã^âVáWÙJÛ^×Ö)á+ç,ã^ã^âSá׿+çnÙXÛ,Úeô& )1çEú\ר',ù^í?Úç,Ö0ÛEyí àáÖnè0×èkÙJÛ,ÖFÙ
+×ÙuêdâVÛWènÕ^ÚÙXè?ááWÙ&ênÛâ7èkÙuÕ0å,×ÛWè Ýáã0Û
¡W¥7¨\¯
í/^ýWý%
üáäà0ê0ÛWà )+ê0ÛnÙuê0Û,âÙuê0ÛàáâVÛkñôMèFרÖ0ç,Ú,ã0Û,ãFÙy×å^Û×è+ànÚÛWçFéWÛ\åá<÷$ ð,ì.ì\í><ùWßþJùäàáâVÛ^íÝ7Þ,ßàáâVÛdç,Ö0å
èáæ+ÛdáÙuê0ÛÝ7Þ,ß9àáâVÛdå.Û^ÚÛnÙy×áÖäæÊÕFÙJç,ÖFÙè 6Û,âVÛdÛ.ã^âVÛWèkèÛ0ås×ÖäùÝþ9,ôMàÛ,ÚÚè?Ù&âVÛWçnÙJÛ\å?×Ùuê þönö Jþ')ÛnÙXáÖ0Û^í7ç
àáæÊæ+Û,âVà0×ç,ÚÚÃçné\ç.×Úç,÷^ÚÛ2×Ö^ê^×÷.×ÙXáâdáð,ì^ì èã^âVÛné,×áÕnè0ÚÅâVÛ,ã0áâSÙÛWå<#×Ùyþ?>áÕnØê0áÕ^ÚÙJÛ
¡^¥Ê¨W¯´
Wý^ýJíMÙuê0Û
×æÊæÊÕ^Ö0á÷^ÚáWÙç,Ö0ç.Ú\èF×èeá ·àÛ,ÚÚè Ù&âVç,Ö0èTXÛWàkÙJÛWå+×ÙuêÙuê0Û dü Þô«õôàáÖ0èµÙ&âJÕnàkÙç,Ö0å2ÙuâVÛWç0ÙJÛWå+×ÙuêÙuê0ÛEð,ì^ì
×Ö^ê^×÷.×Ùáâè0êná6ÛWåÙ&ê0çnÙ+ð,ì^ìàFÚÛWçné\çWØ^Û #çWèÊáÖ^ÚYã0ç,âSÙy×ç,ÚÚ)×Ö^ê.×÷^×ÙÛWåí ÚÛ0çWå×ÖnØsÙXásÙ&ênÛå^ÛnÙJÛWàkÙy×áÖ á+÷náWÙ&ê)ã\ÿ
ç,Ö0å5ã ôLuúnר?ôFÞ%6ð.׿Ê×Úç,âÊâVÛ\ènÕWÚÙè 6Û,âVÛPá÷FÙXç,×Ö0ÛWå ?×Ùyê ><ùWßþùeàkáâVÛã^âVáWÙJÛ^×ÖçÖnåPÙ&ênÛÝ7Þ,ßÃàáâVÛPå^Û^Úÿ
æÊÕFÙJç,ÖFÙ í +ênÛâVÛWçWèÊçàáæÊãWÚÛnÙÛ)×Ö.ê^×÷W×Ù&×áÖäá ðì^ì ànÚÛWçné\çWØWÛ 6çWèÊá÷0èµÛâSéWÛWåGXáâÙuê0Û)ÝÞ,ßPàáâVÛå^Û^Ú%æÊÕFÙJç,ÖFÙ
uúWרMôFÞ üê0ÛWèÛ å^çnÙçeènê0á#ÛWåeÙuê0çnÙÝÞ,ßÅç,Ö0å=><ùWßþù dü àáâVÛeáâdÝ7Þ,ßÅàáâVÛeå^Û,ÚÛnÙ&×áÖæÊÕFÙJçÖ«Ùè #ÛâVÛ
Ûy×àn×Û,ÖFÙ&ÚÊànÚÛ\ç«é\ÛWå÷7ð,ì.ìd×Ö+Ùuê0ÛÊèB0èkÙJÛ,æTÕ0èÛWåê0Û,âVÛ
Î.ª^¯ªÀµ¨0¯n¨Æ¥Çª^dªÄaËÀkª.¢J¡´ -Î<Ë?Àµª^¢J¡Ê¨W^° <Î<Ë?Àkª.¢J¡Ê°\¡W¯¡^¥Çª^ ³W¥Ç¨\,¥£ ¥d¯Í°°^¢Xª«Í¯¡^¥£
HAL author manuscript inserm-00137282, version 1HAL author manuscript inserm-00137282, version 1
+×ÙuêYÚ×ã.×åYåâVáãWÚÛnÙJè Ø.ç0éWÛ)èF׿Ê×ÚçâAâVÛ\ènÕ^ÚÙXès×ÖsÛ×Ùuê0Û,â+ùÝþôáâ+úWöÞàÛ,ÚÚÚ×Ö0ÛÛPâVÛ,ã0áâSÙênÛâVÛPâVÛWènÕ^ÚÙJè×Ö
úWöÞEê0Û,ã0çnÙJáæ+çàÛ.ÚÚèíMèF×Ö0àÛeÙuê0Û2Úá6Û,âÊÛy×àn×Û,Ö0àeáÊÙuê0Û5ð,úßEé\ÛWàkÙJáâVè ×ÖPÙ&ê0ÛWèÛàÛ^ÚÚèeâVÛWènÕ^ÚÙJÛ\å2×ÖPÙuê0Û
ã^âVá^åÕ0àkÙu×áÖPáäÚá#Û,âÌç,æaáÕ^ÖFÙJè)á ã.âVáWÙÛ.×ÖYÙuê0ç,Ö×ÖùÝ ^þ9ôYàÛ,ÚÚèFíAç^ÚÚá+×Ö0Øç5æ?áâVÛ5ã^âVÛWàn×èÛeç,Ö0ç,Ú\èn×è)á
ènÕ^÷0àÛÚÚÕ.Úçâå×èuÙuâJ×÷^ÕFÙu×áÖá6àáâVÛ)ã^âVáWÙJÛ^×Ö0èï×ÚÛâVÛWåYÚç,÷0Û,Ú×ÖnØP×ÖàáÖ«Ù&âVáÚ7úWöÞsàÛ,ÚÚèÊÙuâVçÖFèTXÛWàkÙJÛWå +×Ùuê
βþ?>ç,Ú
Ôï* ènê0á#Û\å Ùuê0çnÙøÚ×ã^×å^è<#ÛâSÛ ÛnéWÛÖ.Ú å×èµÙuâX×÷^Õ«ÙÛWå Ù&ê.âVáÕ0Øê0áÕFÙeÙuê0Û àB0ÙJáã^ÚçWènæ ú0ר)ÿ í ÷0áWÙÉÙáæ
üâVç,Ö0èTXÛWàkÙu×áÖ ?×Ùuê+Ùuê0Û düÏÞôõ7ô+ç,Ö0ådÞô^ÿÊàáÖFèkÙuâJÕ0àµÙèM×ÖFåÕ0àÛWådànÚÕ0èµÙÛ,âJ×Ö0Ø×Ö+Ùuê0Ûäã0Û,âJ×Ö^Õ0ànÚÛWçâ7çâVÛWçÊáÚç,âVØ^Û
Ú×ã^×ååâ¤áã.ÚÛ0ÙÉèCí7èµÙç,×Ö^×Ö0ØäèµÙ&âVáÖ0ØÚXáâ<Ý7Þ,ßYàáâVÛsã^âVáÆÙÛ.×Ö uúnרÿ JíçWèã^âVÛné^×áÕ0èFÚsâVÛ,ãCáâSÙÛWå"#×Ùþ?>áÕ0Øê0áÕ^ÚÙJÛ
¡^¥¨\¯
í^ý.ý Ýáã0Û5ç,Ö0åTò<ànökç,Õ0à0ê.ÚçÖWíWý^ý^ýäò<ànöç,Õ0ànê^Úç,Ö
¡Æ¥¨n¯
í^ýWýTMÝÞ,ß àkáâVÛ5å.Û^ÚÛnÙ&×áÖ5æÊÕFÙJç,ÖFÙJè
Û,Ö0àá^å^ÛWå)÷$Ù&ê0Ûäå^Û,ÚôFíå^Û,Ú^íå^Û.ÚÿçÖnåå^Û,ÚôäàáÖ0èµÙ&âJÕFàµÙèMå×ènãWÚçWÛWåçdèn׿Ì×Úç,âå×èuÙuâJ×÷^ÕFÙu×áÖdçWèÌÞôõôÊç,Ö0å
Þô&^ÿsç,Ö0åPæ+á.èkÙuÚsàáÚá.àç.Ú×ÛWå +×Ùuê)Ú×ã\×å)åâVáã^ÚÛnÙXè úWרÿ. %üê^Õ0èFíç^ÚÚÝÞ,ßeàáâVÛã^âVáWÙJÛ×Önè?×Ùuêå^Û,ÚÛ0Ùu×áÖ0è
+×Ùuê^×ÖPÙuê0Û y×â¤èµÙ9ô\ýç,æÊ×Ö0áçWà0×å.èPâVÛ0ÙJç,×Ö0ÛWåÙ&ênÛ^×âÊç,÷^×Ú×ÙeÙá5çnèèá^àF×çnÙJÛ ?×Ùuê5Ú×ã^×å5åâSáã^ÚÛnÙXèFí +ê^×ànê×èP×Ö
çWØâVÛWÛ,æ+ÛÖ«Ù A×Ù&êã^âVÛné×áÕ0è6áâ5)Õ0è«×Ö0ØYáWÙuê0Û,â6å^Û,ÚÛnÙy×áÖsàkáâVÛPæÊÕFÙJç,ÖFÙJè1 Ýáã0Û)ç,Ö0å ò<à0öçÕnà0ê^Úç,Ö\í ^ý^ýWýTîuÖ
àáÖFÙuâVç\èµÙyíÊÙuê0Û ÝÞ,ß àáâVÛ2å^Û,ÚÛ0Ùu×áÖEæÊÕFÙJç,ÖFÙÛ,Ö0àá^å^ÛWå ÷$5Ù&ênÛøå^Û,Ú %ÃàáÖ0èµÙuâJÕ0àkÙsà0ÚÛWç,âJÚøè0êná6ÛWå ÚçWà)eá
àáÚá^àçÚ×kçnÙu×áÖ"A×ÙuêsÚ×ã^×ååâVáãWÚÛ0ÙJèuúnרÿ 17ÛÚÛnÙu×áÖ %äàáâJâVÛ\ènã0áÖnå^èMÙásçèÛ98Õ0Û,Ö0àÛ +×Ùuê^×Öäå^áæ+ç^×Öîyî#á
Ùuê0ÛYàáâVÛeã.âVáWÙÛ.×ÖsÙ&ê0çnÙ #ç0è)âVÛ,ã0áâSÙÛWå)ÙJá7Xá,ÚåPç0èç ã^ÕFÙJç0Ù×é\Û
αþê0Û,Ú× ù^áÕ^Úç,ÖFÙ ¡Æ¥:¨0¯í ^ý^ý2%MÝáã0Û
¡^¥?¨n¯
í
^ý^ý%?Õ^âå^çnÙç Ùuê^Õ0è2è0Õ0Ø.Ø^ÛWèkÙPÙuê0çnÙÑÙuê^×è ã^ÕFÙJç0Ùu×é\Û
αþênÛÚ× ×è ã.âVá÷0ç,÷WÚ âVÛ98Õ^×âVÛWåUXáâPÚ×ãW×å åâVáã.ÚÛnÙ çWèèá^àF×çnÙu×áÖ7ßÛ,â+ 6ÛWç)è0רÖnç^Úè#Û,âVÛá÷FÙJç,×Ö0ÛWå3Xáâ?æÊÕFÙXç,ÖFÙMã^âVáWÙJÛ×ÖnèdÛ,Ö0àá^å^ÛWåP÷$Ùuê0Ûså^Û,Ú sç,Ö0å)å^Û,Ú%
àáÖ0èµÙ&âJÕ0àµÙJè å^çnÙçäÖnáWÙè0ê0á2+Ö íàáÖ0èn×èµÙÛ,ÖFÙ A×Ù&êMáÕ^â #Û\èµÙJÛ^âJÖd÷.ÚáWÙXÙu×Ö0ØâVÛ\ènÕ^ÚÙXè ú\ר/Jí æ+ç)n×Ö0Ø×Ù׿Êã0á^èkèn×÷WÚÛ
ÙJá)×ÖFé\ÛWèµÙyר^çnÙJÛ àáÚá^àçÚ×ç0Ù×áÖdáÙuê0ÛWèÛæÊÕ«Ùç,ÖFÙ?ã^âVáWÙJÛ,×Ö0è+×ÙuêÚ×ã^×ååâVáãWÚÛnÙèÉÙuêW×è #ç\èMç^ÚèáäÙuê0ÛäàçWèÛ+ê0Û,Ö
Ùuê0ÛWèÛPàáÖ0èµÙ&âJÕ0àµÙJè #ÛâVÛPÛã.âVÛ0èèÛWå×ÖeùÝþ9,ô)àÛ,ÚÚè?% è)ã^âVÛné,×áÕ0èFÚâVÛãnáâSÙÛWåI Ýáã0Û
¡^¥+¨W¯
í Wý^ýJíaÙ&ê0Û
><ùWßþùYàáâSÛPã^âVáWÙJÛ^×Ö6çWèdàB0ÙJáãWÚçWè0æM×àCí å×è0ã^Úç7\ÛWåYçPâVÛnÙy×à«Õ^ÚçnÙÛPã0çnÙÉÙÛ,âJÖsàáæÊãnç0Ù×÷^ÚÛ A×Ù&êsç0èèká^àn×çnÙy×áÖ A×Ùuê
ñ,Ôæ+Û,æÊ÷^âVç,Ö0ÛWèíçÖnådàáÚá^àç^Ú×ÛWåA×Ù&êÊÚ×ãW×ååâVáã^ÚÛnÙXè uúnר^ÿ,ùT
¯¥Ç¢J¨£W¥V¢&³ÆÀ¥J³n¢J¨W¯-À ^¨W¡F£)¨W^° ËnÓ Çª^¢Ê¨^¥Vª^P^°³WÀk¡W°P®e¥^¡Y¡ nÍ¢J¡F££nª.ѪAÄ aËÃÀµª^¢J¡k´ -Î<ËÀµª^¢J¡´ª.¢
-Î<Ë?Àµª^¢J¡Ê°^¡W¯¡^¥Çª^ ³W¥Ç¨\,¥£
0ÚÙuâVç0èµÙ&âJÕnàkÙuÕ^âVç,Ú0ànê0ç,Ö0Ø^ÛWè?á÷0èÛâSéWÛWå×ÖdùÝ þ9ôAàÛ,ÚÚè#Ù&âVç,Ö0èTVÛ\àµÙJÛ\å,+×ÙuêdâVÛWàáæÊ÷^×Ö0ç,ÖFÙð,úßéWÛ\àµÙJáâVèCíç0è?èµÙ&Õ0å×Û\å
÷$)Úá?þæ+ç\ØÖ\××àçnÙu×áÖsñ,ò í 6Û,âVÛàáÖ0èF×èµÙÛ,ÖFÙ&?×ÙuêsâVÛ\ènÕ^ÚÙXèMá÷FÙJç,×Ö0ÛWåY÷7·àáÖ?Éá^àç.ÚæÊ×ànâVáWèàáã$Ü çÚÚÝ7Þ,ßÑàáâVÛ
æÊÕFÙJç,ÖFÙèMê0ç,âJ÷0áâJ×Ö0Ødå^Û,ÚÛnÙu×áÖ0è+×ÖMå^áæ+ç,×ÖîJå.ÛÚ,ô0íå^Û,Ú .í,å^Û,Ú\ÿÊç,Ö0åå^Û,Úô å×ènã^Úç \ÛWåçÊè0׿M×Úç,âãnç0ÙÉÙJÛâJÖMçWè
Ùuê0çnÙÌá ÊüøàkáâVÛeã^âVáWÙJÛ^×ÖnèÞô«õôç,Ö0åPÞô&Wÿ^í è0ê0á2+×Ö0Øà0ÚÕ0èµÙÛ,âVèáMÚ×ã.×åÑåâ¤áã.ÚÛ0ÙÉè×ÖsÙuê0ÛeãnÛâJ×Ö.Õ0à0ÚÛWç,â6ç,âVÛWç
uúWר^è^ç^í÷Wí%0ç\í%^÷ç,Ö0åLÆç <å^çnÙçÖ0áWÙ6ènê0áAÖXáâ<å^Û^Úô %ð,׿M×Úç,â6âVÛWè0Õ.ÚÙXè#ÛâVÛsá÷FÙÉç×ÖnÛ\åP×ÖsùÝþ9ô
àÛÚÚèMã^âVá.åÕ0àn×Ö0Ø><ùWßþ ùdàáâVÛäã^âVáWÙJÛ,×Ö ú\רWç%î ÖÌàÛ,ÚÚèMã^âVá^åÕ0à0×ÖnØ dü)Þô«õô+àáâVÛ^íå^Û.Úô0íå^Û,Ú ^íå.ÛÚ,ô Wíáâ
å^Û,Ú6ÿ2ÝÞ,ßTàáâVÛøæÊÕFÙJç,ÖFÙJèYáâMÙuê0Û ><ùWßþù5àáâVÛøã^âVáÆÙÛ,×Ö\í:Ù&ênÛ\èÛà0ÚÕ0èµÙJÛâVèáÚ×ã^×å5åâVáã\ÚÛnÙJè #ÛâVÛç,Ú6ç 0è
ènÕ^âJâVáÕ^Ö0å.Û\å÷$YÛ,ÚÛWàµÙ&âVáÖWþÉå^Û,Ö0èÛ^í#àáÖFé0áÚÕFÙJÛWåñ^Ô5æ+Û,æÊ÷^âVç,Ö0ÛWè"uúWר^è&^ç^í %0ç^í%0íÉ÷Wí ÆçYç,Ö0å Wç ?å^çnÙJçeÖ0ánÙ
ènê0á+ÖÉáâ<å^Û,Ú ô üê0Û!yâVÛ98Õ0Û,Ö0àBá6àÛ,ÚÚè,+×Ùuêè0Õnà0êsñÔçÚÙJÛ,â¤çnÙu×áÖFè#ç\èÊèn׿Ê×ÚçâXáâaÝ7Þ,ß Êüáâ<àáâVÛ
å^Û,ÚÛnÙ&×áÖsæÊÕFÙJçÖ«ÙèFí Aê0Û,âVÛWç\èäñ,Ô)à0ênçÖnØ^ÛWè46Û,âVÛá÷0èÛ,âSé\ÛWå)ÚÛWèè yâVÛ98Õ0Û,ÖFÙuÚ9×ÖäàÛÚÚèÊÛã^âVÛWèkèn×Ö0Ø><ùWßþ ùàáâVÛ
ã^âVáWÙJÛ,×Ö6Süç,÷WÚÛTô& <üê0ÛEÕ^ÚÙuâVç\èµÙuâJÕ0àkÙuÕ^âVç,Ú?æ+á^å×J×àç0Ùu×áÖeáÊÙuê0ÛEñ^Ô ×ÖàÛÚÚèeã.âVá^åÕ0àn×Ö0ØTÝ7Þ,ß àáâVÛEæÊÕFÙJç,ÖFÙ
ã^âVáWÙJÛ,×Ö0è?Û,Ö0àá.å^ÛWå÷$MÙ&ênÛÊå^Û,Úô ú\ר/%0çyíå^Û,Ú úWר *%^÷ ç,Ö0ådå^Û,Úô Ö0áWÙènê0á+ÖàáÖ0èµÙ&âJÕnàkÙJè 6çWè?è0׿Ê×Úç,â
HAL author manuscript inserm-00137282, version 1HAL author manuscript inserm-00137282, version 1
Ùuê0ÛÝÞ,ß)å^Û,Ú\ÿàáâVÛäæÊÕFÙJçÖ«Ù6ã^âVánÙÛ,×ÖMáâÙuê0Û,>ùWßþùàáâVÛãWâVáWÙÛ,×Ö XáâJæ+ÛWåçÊÙuÕ^÷^Õ^Úç,â #Û÷úWרWè 5çÖnå"TîuÖ
àáÖFÙuâVç\èµÙyíàáÖnèF×èkÙJÛ,ÖFÙ A×Ù&êáÕ^â?ã^âVÛné^×áÕ0è×Ö0å,×Ö0Ø^è #×Ùþ?>á,Õ0ØênáÕ^ÚÙJÛ
¡^¥<¨W¯
í^ý^ý?ùÚç,Ö0ànê0ç,âVå
¡^¥<¨W¯´
^ýWý^ÿyí
Ùuê0Û düfÝÞ,ßÑÞô&.ÿàáâVÛ)ã^âVáÆÙÛ.×Ö å×åÖ0áWÙ6àç,Õ0èÛç,Ö$è0ã0Ûnà0××àäÕ^ÚÙ&âVçWèµÙ&âJÕnàkÙuÕ^âVç,Úæ+á^å××àçnÙ&×áÖäáÙ&ê0ÛÏñÔLuúWר
÷ í7ç\èAå×åÙ&ê0ÛÛã^âVÛnèèF×áÖá -×âJâVÛ,ÚÛné\ç,ÖFÙ
βþ?>çÚuÖnáWÙè0ê0á9AÖ %ð,׿Ê×Úç,âÉÚ\íÖná ènã0ÛWàn×y×àÊÕ^ÚÙuâVç0èµÙ&âJÕnàkÙuÕ^âVç,Ú\ànê0ç,Ö0Ø^Û áÙuê0Ûñ,Ô 6çnè+á÷FèÛ,âSéWÛ\ås×ÖÊàÛ^ÚÚèÊã^âVá^åÕnà0×Ö0ØÙuê0ÛÝ7Þ,ß9àáâSÛæÊÕFÙJç,ÖFÙèAÛÖnàá^å.Û\ås÷$ÊÙuê0Ûå^Û,Ú&Guú0ר/ nçyí7å^Û.Ú%
uúWרWà?+ç,Ö0åå^Û,Ú%> Ö0áWÙ+ènê0á+ÖsçnÙÌÚá æ+çWØÖ^×y×àçnÙy×á,Ö +àáÖ0èµÙuâJÕ0àkÙJèFí?÷^ÕFÙ?Ùuê0Û)àB0ÙJáã^ÚçWè0æ²á#Ù&ênÛ\èÛ)àÛÚÚè
àáÖFÙJç×ÖnÛ\åfÖ0áÖ\þÉèµÙ&âJÕnàkÙuÕ^âVÛWåeÛ^ÚÛWàµÙ&âVáÖ\þÉå^Û,Ö0èÛæ+çnÙXÛ,âJ×ç.Ú; Eã0ç,âSÙu×à0Õ^Úç,âJÚæ+ç,â5)ÛWåPàÛÚÚ×Ö uÕ^â+Æí#çWè)×Ö0å×àçnÙÛWå÷$
Ùuê0Ûã^âVÛWèÛ,Ö0àÛá<Úç,âVØ^ÛÊéWç\ànÕ0áÚÛWèCí#ç0è+á÷FèÛ,âSé\ÛWås×ÖàÛ,ÚÚèã\âVá.åÕ0àn×Ö0ØÙ&ê0Ûå^Û,Ú G ú\רWçáâÙuê0Ûå^Û,Ú %uÖFáWÙ
ènê0á+ÖäçnÙ+Úá2 æ+çWØÖ.××àçnÙ&×áÖ AÝÞ,ßYàáâVÛå^Û,ÚÛnÙu×áÖsæÊÕFÙç,ÖÙJè ^üê.×èÊàÛ.ÚÚ×Ö uÕ^â+)æaá^èµÙ+ã^âVá÷Fç,÷^ÚäÛ&,ã^Úç^×ÖnÛ\åÙuê0Û
ã0á^áâå^ÛnÙÛWàµÙ&×áÖMáÙuê0ÛWèÛäæÊÕ«Ùç,ÖFÙ<ã^âVáWÙJÛ^×ÖnèÌ÷7 #Û\è ÙÛ,âJÖd÷.Úá0Ù ú\ר/%
Ùaê.רê0Û,â<æ+çWØÖ^×y×àçnÙy×áÖ\íàÛ^ÚÚèã^âVá^åÕ0àn×Ö0ØäÙuê0ÛsÝÞ,ßYàáâVÛÊå^Û,ÚÛnÙ&×áÖæÊÕ«Ùç,ÖFÙJèÌÛ,Ö0àá^å^ÛWå)÷7ÊÙ&ê0Ûäå^Û,Úô0í
å^Û,Ú ç,Ö0å²å^Û,Ú ô% àáÖCèµÙuâJÕ0àkÙJèøå.Ûæ+áÖ0èkÙuâVçFÙJÛWå ê^רê²ÚÛné\Û,Úè5áeÝÞ,ßþönìTç\èµèÛ,æÊ÷^Ú çnÙÑàáÖFéWáÚÕ«ÙÛWå ñÔ
æ+Û,æÊ÷^âVç,Ö0ÛWèJç,âJâVá<èÊç,Ö0å)×ÖnèÛnÙJèÌáÖú\ר.è& %nàí %nåç,Ö0å %nÛ yí Ú×)Ûs×Ö àÛ,ÚÚèäã.â¤á^åÕ0à0×ÖnØÊüeÞôFõôúWר^àÊç,Ö0å
üç,÷^ÚÛYô&TüênÛçWèkèá^àF×çnÙu×áÖá 6àáâVÛã^âVánÙJÛ×Ö ?×ÙuêäÙuê0ÛWèÛ)æ+Û,æÊ÷^âVç,Ö0ÛWè,6çWèdàáÖ?y×âJæ?ÛWåP÷$)×æÊæÊÕ^Ö0áþÉÛ,ÚÛWàµÙ&âVáÖ
æÊ×ànâVá^èàáã$Iç\è)ènê0áAÖeç0èÛ&Wç,æÊã\ÚÛWè3XáâÌÙuê0Û2ÝÞ,ß üTç,Ö0å5å^Û,Ú$eàáâVÛ2ã^âVáWÙJÛ^×Ö0èP×Ö5únר^è$^å5ç,Ö0å%.Çí
âVÛWè0ãnÛ\àµÙu×é\Û^Ú%,üê0Û)ã^âVÛWèÛ,Ö0àÛá+âJ×÷Fá^èkáæ+ÛWèÊçnÙ6Ùuê0Û^×âè0Õ.âXçWàÛuúWרWè^ÛçÖnå"^Ø5?ç,Ö0åsÙ&ênÛ^×â<àáÖFÙy×Ö^Õ^Õ.æ A×Ù&ê
Ùuê0ÛäáÕFÙJÛâ<æ+Û,æÊ÷^âVç,Ö0ÛäáÙ&ê0ÛsÖ,Õ0ànÚÛ\ç,âÛ,ÖFéWÛÚáã0ÛGuúWרGfè0êná6ÛWå)Õ^ÖnçæÊ÷.רÕ0áÕ0ènÚdÙuê0çnÙÙuê0ÛWèÛsæ+Û,æÊ÷^âVç,Ö0ÛWè
6Û,âVÛEñ,ÔþâVÛ.Úç0ÙJÛWå<üêW×èe×è ×Öeç\ØâVÛ\Û,æ+Û,ÖFÙ +×Ùuêøã^âVÛné×áÕ0èèkÙuÕ0å×ÛnèCíMènê0áA×Ö0ØÙuê0çnÙ Ùuê0ÛEÝÞ,ßTàáâVÛEã^âSáWÙJÛ×Ö
àáÚá^àçÚ×Û0ès×ÖYã0ç,âSÙ+×ÙuêYÚ×ãW×ååâVáã^ÚÛnÙXèäç,Ö0åe×Öã0ç,âSÙ+×ÙuêYñ,Ôæ+ç,â5)Û,âVèäènÕ0à0êsçWè àç,ÚâVÛWØÕ^Ú×Ö>yðÕ0Õ2)0×
¡^¥#¨W¯´
^ý^ý(% % Úèá^í)Û,ÚÛWàkÙuâVáÖ æÊ×ànâSá^èàáãW×àEèkÙuÕ0å×ÛWèEá7yÚçné^×é^×âXÕ0èFþ×Ö?XÛWàµÙÛWå àÛ,ÚÚè ê0çné\Û²àáÖ0èn×èµÙJÛÖ«Ù&Ú á÷0èÛ,âSéWÛ\å
æ+áâJã^êná^Ø×àçÚÚPæ+ç0ÙuÕ^âVÛsé^×âJ×áÖFè+×Ùuê^×ÖÙ&ê0ÛPÚÕ.æ+ÛÖsáaç)àáæÊã0ç,âSÙuæ+Û,ÖFÙ?Ù&ê0çnÙ+ç,ã^ã0ÛWç,â<ÙJáe÷0ÛPâVáÕnØêYñ,ÔÑáâa×Ö
é\ÛWèn×à0ÚÛWèMÚ×Ö)ÛWåÊÙJáÊÙuê\×è?àáæÊã0ç,âSÙuæ+ÛÖ«Ù Ô×àÛ^íôõ.õ
îuÖYàáÖFÙuâVçWèkÙyí?àÛ,ÚÚèã^âVá^åÕnà0×Ö0Ø Ù&ê0ÛÝÞ,ßøàáâVÛPå^Û,ÚÛnÙ&×áÖeæÊÕ«Ùç,ÖFÙÊÛ,Ö0àá.å^ÛWå5÷$YÙuê0ÛPå^Û,ÚÿPàáÖ0èµÙ&âJÕnàkÙ
ènê0á6ÛWå Ö0á²ÝÞ,ßþönì ÷.Õ0å^å×Ö0Ø ç0Ù)Ùuê0Û,×âäÙuÕ^÷^Õ^Úç,âXíäÛ,ÚÛWàkÙuâSáÖ\þÉå^Û,Ö0èÛ²ñ,Ô æ+Û,æÊ÷^âVç,Ö0ÛWè6 úWר\è,÷Eç,Ö0å Wà?yí
ç,ÚÙ&ênáÕ0ØêäÚç,âVØ^ÛÊç,æ+áÕ^ÖFÙJè?á<ÝÞ,ßå^Û,Ú\ÿàáâSÛ6Û,âVÛäã^âVÛWèÛ,ÖÙ#×ÖÌÙuê0ÛWèkÛÙ&Õ^÷.Õ^Úç,âñÔsæ+Û,æÊ÷^âVç,Ö0ÛWèí7ç0è+àáÖ?×âJæ+Û\å
÷$P×æÊæÊÕ^Ö0áþÉÛ,ÚÛWàµÙ&âVáÖæÌ×ànâVá^èàáã$2úWר Æå%üê0ÛWèÛsÙ&Õ.÷^ÕWÚçâAæ+ÛæÊ÷.âVçÖnÛ\è#ÛâVÛ)ç.ÚèkáYàáÖFÙu×Ö^Õ0áÕ0è?×Ù&êÙ&ê0Û
áÕFÙJÛ,âæ+Û,æÊ÷^âVç,Ö0ÛáÙ&ênÛäÖ^Õ0ànÚÛ\ç,âÛ,ÖFé\Û.Úáã0Û úWר,÷ yíè0êná.A×Ö0ØÙ&ênç0ÙÙ&ê0Û 46Û,âVÛäñ,ÔþâVÛ,ÚçnÙÛWå,ÞÛ^ÚÚèÊã^âVá^åÕnà0×Ö0Ø
Ùuê0ÛÝÞ,ß)àáâVÛdå^Û,ÚÛnÙu×áÖäæÊÕFÙç,ÖFÙJè+Û,Ö0àá^å^ÛWås÷$ÊÙuê0Ûdå^Û,Úí7å^Û,Ú%Êç,Ö0åäå^Û,Ú%ÊàáÖ0èµÙ&âJÕ0àµÙJè+è0êná6ÛWåsÖ0ásÝÞ,ßþö0ì
çWèèÛ,æÊ÷^Ú ú\רWè ,÷WíWå2çÖnå<WÛ ÊÝ7á6Ûné\Û,âXíÙ&ê0ÛEã.âVÛ\èµÛÖnàÛ5áÙ&ênÛEÝÞ,ß àáâVÛ5å^Û,ÚÛnÙu×áÖøæÊÕFÙJç,ÖFÙJè×Öç
àB0ÙJáã^ÚçWè0æM×àFí#Ö0áÖ\þÉèµÙ&âJÕnàkÙuÕ^âVÛWå)Û,ÚÛ\àµÙuâVáÖ\þÉå^Û,Ö0èÛYæ+çnÙJÛ,âX×ç,Ú×ÖäÙuê0ÛWèÛàÛ,ÚÚè Jç,âJâSá6èç,Ö0åP×Ö0èÛ0ÙÉè×Ö)úWרWè ,÷0í'Wå
ç,Ö0å"WÛ 6çWèdÕ.Ö0ç,æÊ÷^רÕ0áÕnèFÚ å^Û,æ+áÖnèkÙuâ¤çnÙJÛWå)÷$×æÊæÊÕ.Ö0áWÛÚÛWàµÙ&âVáÖæÊ×à0âVáWèàáã$1 ç\èAè0ê0á2+ÖXáâÛ&Wç,æÊã\ÚÛ0Xáâ
Ùuê0Û5ÝÞ,ßEå^Û,Ú&%YàáâVÛ5ã^âVánÙJÛ,×Öe×ÖúWר %:ïáPé×âJÕnèCþÚ×)Ûã0ç,âSÙu×à0ÚÛnè 6Û,âVÛPá÷0èÛâSéWÛWå5×ÖYÙuê0ÛWèkÛeàB0ÙJáãWÚçWè0æM×à
èµÙ&âJÕ0àµÙuÕ^âVÛWèàáÖFÙJç,×Ö^×Ö0Ø5ÝÞ,ß5àáâVÛPå^Û^ÚÛnÙu×áÖ æÊÕFÙç,ÖFÙJè6úW×ÖFç,ÚÚ\íMÖ0áé×âJÕnèCþÚ×)Û ã0ç,âSÙ&×àFÚÛ@#ç0èså^ÛnÙÛWàµÙÛWå×Ö)Ùuê0Û
Û,ÚÛWàkÙuâVáÖ\þÉå^Û,Ö0èÛsñÔPæ+Û,æÊ÷^âVç,Ö0ÛnèäÖ0áâ<×ÖÙ&ê0ÛsÚÕ^æ+Û,Öäá<àÛ,ÚÚèÊÛã.âVÛ0èèF×Ö0ØÙ&ê0Û ><ù0ßþùsàáâVÛã.âVáWÙÛ.×Ö1 ú0ר,÷ yí
å^ÛWènã^×ÙÛ)ÛnÙÛ,Ö0èF×éWÛP×ÖFé0ÛWèkÙuרWçnÙ&×áÖ7üê0ÛPã^âVÛWèÛ,Ö0àÛ)á ><ùWßþJùàáâVÛPã.âVáWÙÛ,×Ö×ÖÙuê0ÛWèÛ)å^Û,Ö0èÛPñ,Ôæ+Û,æÊ÷^âVç,Ö0ÛWè
àáÕ^ÚåÖ0áWÙd÷nÛYàáÖ?y×âJæ+ÛWå÷$P×æÊæÊÕ^Ö0á^Û,ÚÛWàkÙuâVáÖPæM×à0âVá^èàáã7YåÕ0Û)ÙJáã0á^áâ?çWàkÙ×é×ÙYá?Ùuê0ÛYç,ÖFÙu×þ?>ùWßþùÑàáâSÛ
ç,ÖFÙu×÷0á^å9ä×ÖdâVÛnè0×Ö\þÉÛ,æÊ÷0ÛWå^å.Û\åàÛ,ÚÚè&
HAL author manuscript inserm-00137282, version 1HAL author manuscript inserm-00137282, version 1