MOLEKULARNI MEHANIZMI UKLJUČENI U NASTANAK STRESA ENDOPLAZMATSKOG RETIKULUMA – ŠTA ZNAMO DO SADA
Sažetak
Endoplazmatski retikulum (ER) predstavlja intracelularnu organelu koja ima ulogu u sintezi i obradi proteina. Kada dođe do narušavanja ravnoteže između potreba ćelija za proteinima i kapaciteta ER za obradu proteina, nefunkcionalni, pogrešno uvijeni ili neuvijeni proteini počinju da se nakupljaju u ER dovodeći do nastanka stresa endoplazmatskog retikuluma (ER stresa). Jedan od načina kojim ćelija prevazilazi ER stres je pokretanje UPR (engl. unfolded protein response). UPR se pokreće kada dođe do aktivacije tri proteina koji se nalaze u membrani ER. Reč je o IRE-1α (inositol requiring enzyme-1α), PERK (protein kinase RNA-like endoplasmic reticulum kinase) i ATF6 (activating transcription factor 6) koji se aktiviraju kada se od njihovog luminalnog domena odvoji ER šaperon GRP78. Aktivacijom ova tri transmembranska senzora pokreću se mehanizmi čiji je cilj obnova funkcije ER. Ukoliko funkcija ER ne bude obnovljena i ukoliko se ne dostigne stanje ravnoteže, pokreće se proces apoptoze kako bi se osigurala ćelijska homeostaza. Aktiviran IRE-1α dovodi do obrade iRNK koja kodira transkripcioni faktor XBP-1 (X-box binding protein-1) i do aktivacije mitogenom aktiviranih kinaza (MAPK) i inflamatornih puteva koji uključuju NFƙB. Aktiviran ATF 6 (ATF6f) funkcioniše kao transkripcioni faktor i povećava ekspresiju gena za XBP-1, dok PERK dovodi fosforilacije, a time inaktivacije eukariotskog faktora inicijacije translacije 2 (eIF2α), što za posledicu ima smanjenu sintezu proteina. Fosforilacija eIF2α dovodi i do selektivne sinteze trasnkripcionog faktora ATF4 koji kod ireverzibilno oštećenih ćelija dovodi do aktivacije ćelijske smrti pokretanjem transkripcije gena za CCAAT-enhancer binding protein homologous protein (CHOP).
Poznato je da ER stres i UPR imaju značajnu ulogu u patogenezi različitih bolesti među koje spadaju dijabetes, inflamacija, tumori i neurodegenerativne bolesti. Poznavanje signalnih puteva UPR, kao i mehanizama kojima je UPR uključen u patogenezu ovih bolesti može biti od velikog značaja u razvoju ciljanih terapeutskih pristupa za lečenje ovih bolesti.
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