apoptozis regulacia IAP ojaxis wevrebiT IAP –

inhibitor of apoptosis
Uujredis sikvdili - apoptozi da nekrozi

apoptozis regulacia IAP ojaxis wevrebiT

IAP – inhibitor of apoptosis

IAP ojaxis wevrebs warmoadgenen

cIAP1 livini

cIAP2 NAIP

XIAP

apoptozis inhibireba aZlierebs kibos ujredebis gadarCenas da aadvilebs

maT Tavis daZvrenas citotoqsiuri Terapiidan. apoptozis regulacias
axdens genTa 2 ojaxi, Bcl-2 da inhibitor of apoptosis (IAP).

ratom aris samizne IAP...?

zogierTi IAP eqspresirdeba specifiurad an gansakuTrebiT maRali

koncentraciiT kibos ujredebSi. zogi IAP eqspresir-deba sxvadasxva
warmoSobis kibos ujredebSi (filtvebi, mkerdi, kani, hematologiuri
kiboebi da sxva). IAP genebi pirvelad aRmoaCines bakulovirusiT
inficirebul mwerebis SF-21 ujredebSi. Aam axal inhibitors SeeZlo
inficirebuli ujredebis apoptozuri sikvdilis inhibireba.

misi geni 1.6 kb aris zomiT da akodirebs 31 kda cilas, romelsac gaaCnia
TuTiis TiTebis msgavsi motivi. Semdgomi kvlevebiT am ojaxSi daagjufes
is cilebi, romlebSic nanaxi iqna 1-dan 3-mde bakulovirusis IAP –is (BIR)

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domenebi N-kidra aminoboloze. zogierT IAP-s aseve aqvs RING (really interesting
new gene ) TiTebis domeni C-kidura boloze.

BIR domeni Sedgeba daaxloebiT 70 aminomJavuri naSTisagan, romlebic

Seicaven damaxasiaTebel Tanamimdevrobas CX2CX16HX6C. zogierT IAPs –Si RING
TiTebis domeni (C3HC4) moTavsebulia C-boloze. is Seicavs erTi TuTiis
atoms dakavSirebuls 3 cisteinsa da erT histidinTan da meore TuTias
dakavSirebuls 4 cisteinTan.

Savad aRniSnulia TuTiasTan urTierTmoqmedi aminomJavuri naSTebi. am

ojaxis zogi wevri aseve Seicavs sxva struqtu-rebsac, rogoricaa kaspazis
aqtiobis SemzRudavi domeni (CARD), fosfatis yulfi (maryuJi), ubiqvitiniT
konugirebadi (UBA) Tanamimdevroba. miuxedavad imisa rom IAP ojaxis cilebis
BIR domeni aucilebelia antiapoptozuri funqciisa-Tvis, BIR Semcveli yvela
cila ar flobs antiapoptozur funqcias.

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 apoptozuri cilis
X-dakavSirebuli inhibitori

adamianis apoptozis
inhibitori cila-1

adamianis apoptozis
inhibitori cila -2

neironuli apoptozis
inhibitoruli cila
survivini

livini

apoptozis progresi regulirdeba Tanamimdevrulad sasignalo kaskadebis

seriiT garkveul pirobebSi. 3 ZiriTadi faqtori IAP, IAP- antagonistebi da
kaspazebi CarTulia am progresis regulirebaSi.

IAP warmoadgens kaspazebis endogenur inhibitorebs. igi moqmedebs

kaspazebis gaaqtivebis Semdeg gzebze:

1)Sida-mitoqondriuli gza;

2) sikvdilis receptorebis gza;

3) endoplazmuri retikulumis stresiT inducirebuli gza, romelic

iwvevs kaspazebis 2 da 9 gaaqtivebas.

Tanamedrove kvlevebiT nanaxia, rom IAP –s SeuZlia kaspazebis aqtiobis

dainhibireba, misi konservatiuli BIR domenis dakavSirebiT kaspazis aqtiur
saitTan rogorc in vitro ise in vivo. Kisini kaspazebis ihibirebas axdenen
aqtiuri kaspazebis degradirebiT, an kidev kaspazebis izolirebiT maTi
substratebisagan. Fas/caspase-8 apoptozur gzaSi IAP ar ukavSirdeba kaspaza-
8-s, magram ainhibireba mis substrat kaspazas-3-s.

IAPs kaspazebis supresirebis rols 3 ziT axorcielebs kaspa-zebis

gaaqtivebis mitoqondriul gzaSi:

1. konkurentulad ukavSirdeba prokaspaza9-s da xels uSlis apoptosomis

warmoqmnas.

2. uSualod ukavSirdeba kaspaza-9-s

3) uSualod ukavSirdeba kaspaza3-s.

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XIAP aris erT-erTi yvelze kargad daxasiaTebuli inhibitori. Xiap (X-Linked
Inhibitor of Apoptosis Protein ) Sedgeba 498 aminomJa-visagan (~55 kDa) igi iTvleba
yvelaze Zlier endogenur inhibitorad. Mmas aqvs 3 BIR domeni: BIR1, BIR2 da
BIR3, romlebic gamoirCevian kaspazebisadmi maRali aqtiobiT, magram
araerTnairi funqciiT. D BIR2 domeni da BIR1–isa da BIR2–is damakavSirebeli
regioni specifiurad ukavSirdeba da ainhibi-rebs kaspaza3-s da kaspaza-7-s.
BIR2 domeni Tavsdeba kaspaza3-is aqtiur saitTan da mis aqtiobas ainhibirebs
substratis-damakavSirebeli jibis blokirebiT. BIR1-2 fragmentis
zeeqspresia mniSvnelovan rols TamaSobs Fas/kaspaza-8-iT ganpirobebul
apoptozSi. Kkaspaza-9-is inhibirebisaTvis IAP saWiroebs rogorc BIR3 aseve
RING domens.

kaspaza9-s aqtiur saitTan fizikuri dakavSirebis gareSe, BIR3 domeni

warmoqmnis heterodimers monomerul kaspaza9-sTan, rac xels uSlis
kaspaza9-is dimerizaciasa da gaaqtivebas. kaspaza-9-is datyvevebiT
monomerul formaSi, BIR3 domeni kaspaza9-is aqtiur saits araaqtiur
formaSi inarCunebs.

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endoplazmuri badis stresiT gamowveuli apoptozuri gzis dros, IAPs
ainhibireben kaspaza-2-s da kaspaza-9-s maTi BIR domenis dakavSirebiT.
endoplazmuri badis roli gansakuT-rebiT kritikulia rogorc gare, ise
Sida apoptozur gzaSi. kaspaza-2, romelic lokalizebulia endoplazmur
retikulum-ze, kaspaza-9-sTan erTad warmoadgens er-is stresiT gamowve-
uli apoptozis mediators. isini aaqtiveben kaspaza 3-s da 7-s. miuxedavad
imisa, rom zog IAPs –s SeuZlia kaspaza 3,7,da 9-is dakavSireba da inhibireba,
mxolod ujreduli IAP 2 (c-IAP2) ukavSirdeba kaspaza2-s uSualod BIR2
domeniT da ainhibirebs mas.

neironuli apoptozis inhibitorul cilaze (NAIP) Catarebulma kvlevebma

aCvena misi antiapoptozuri funqcia rogorc in vivo ise in vitro pirobebSi.
kaspaza 3 da 7-ze ganxorcielebuli inhibitoruli aqtiobis garda, NAIP mis
BIR3 domens iyenebs kaspaza 9-sTan urTierTobisaTvis atf damokidebuli
gziT.

IAP da ubiqvitinirebis procesi

IAP -s BIR domenis kaspazastTn dakavSirebis garda, inhbito-ruli efeqtis

regulireba SeuZlia ubiqvitinirebis procesiT. ubiqvitinireba aris cilis
posttranslaciuri modifikacia, romelic mniSvnelovan rols TamaSobs
apoptozSi da signalis gadacemaSi. Uubiqvitin gamaaqtivebeli (E1), ubiqvitin
makoniugi-rebeli (E2) fermentebisa da ubiqvitin proteinligazas moqme-
debiT samizne cilas ebmeba ubiqvitini. Aamis Semdeg isini Seicnobian da
degradirdebian garkveuli proteosomebiT. IAP-is RING domenis C-bolo
identificirebulia, rogorc ubiqvi-tin ligazas moqmedebis arsebiTi
motivi, romelic aucile-belia ubiqvitinirebisaTvis da proteosoma-
ganpirobebuli Sem-dgomi proteolizisaTvis.

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giganturi BIR domenis Semcveli cila BRUCE aris IAP ojaxis unikaluri
wevri, romelic ormagi roliT aris cno-bili. Mmis N-kidura BIR domens
SeuZlia substratTan dakav-Sireba, xolo C-kidura UBC domeni
uzrunvelyofs E2 aqtio-bas. BRUCE-s aqvs araCveulebrivi sistema
ubiqvitiniT koni-ugirebisaTvis. aq erT polipeptidSi axdens E2/E3
aqtiobebis gaerTianebas da miiReba qimeuli E2/E3 ligaza. autoubi-
qvitinirebiT zogierTi IAPs negatiurad aregulirebs Tavis Tavs. es
procesi inhibitoris degradirebasa da apoptozis progresirebas iwvevs.

IAP Dda IAP antagonistebi

aRmoCenilia mravali mniSvnelovani iseTi faqtori, romlebic

ewinaaRmdegebian IAP–is inhibitorul efeqtebs. Eeseni arian mravalnairi
endogenuri proapoptozuri cilebi, romlebic TiTqmis yvela IAP–ze
moqmedeben.dReisaTvis IAP–sa da IAP–is antagonistebs Soris neitralizacia
sul ufro da ufro xdeba kibos mkurnalobasTan dakavSirebuli kvlevebis
“mania”. es cilebi pirvelad drozofilaSi iqna aRmoCenili da uwodes
Reaper, Grim, Hid, da Sickle da nanaxi iqna rom isini ukav-Sirdebodnen da
ainhbirebdnen DIAP1 -s. mogvianebiT analo-giuri antagonistebi
identificirebul iqna ZuZumwovrebSic: Second mitochondrial activator of
caspases/direct IAP binding protein with low pI (Smac/DIABLO) da High-temperature-regulated
A2/Omi (HtrA2/ Omi), romlebic mitoqondriuli warmoSobis cilebia. mitoqon-
driis daSlis dros apoptozSi CarTuli 40-ze meti regula-tori, Tu
monawile Tavisufldeba misgan, gamodis citozolSi citoqrom c –s,
endonukleaza G–s, IAP da Smac/DIABLO, HtrA2/ Omi-sTan erTad. Ggamoyofis

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Semdeg Smac/DIABLO da HtrA2/Omi ixliCebian da Rebuloben TavianT aqtiur
formas: TaRis magvar dimers da piramidis magvar homotrimers Sesabamisad.