Details

Autor(en) / Beteiligte

• Márton, Margita
• Bánhegyi, Gábor
• Gyöngyösi, Norbert
• Kálmán, Eszter Éva
• Pettkó‐Szandtner, Aladár
• Káldi, Krisztina
• Kapuy, Orsolya

Titel

A systems biological analysis of the ATF4‐GADD34‐CHOP regulatory triangle upon endoplasmic reticulum stress

Ist Teil von

• FEBS open bio, 2022-11, Vol.12 (11), p.2065-2082

Ort / Verlag

England: John Wiley & Sons, Inc

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• Endoplasmic reticulum (ER) stress‐dependent accumulation of incorrectly folded proteins leads to activation of the unfolded protein response. The role of the unfolded protein response (UPR) is to avoid cell damage and restore the homeostatic state by autophagy; however, excessive ER stress results in apoptosis. Here we investigated the ER stress‐dependent feedback loops inside one of the UPR branches by focusing on PERK‐induced ATF4 and its two targets, called CHOP and GADD34. Our goal was to qualitatively describe the dynamic behavior of the system by exploring the key regulatory motifs using both molecular and theoretical biological techniques. Using the HEK293T cell line as a model system, we confirmed that the life‐or‐death decision is strictly regulated. We investigated the dynamic characteristics of the crucial elements of the PERK pathway at both the RNA and protein level upon tolerable and excessive levels of ER stress. Of particular note, inhibition of GADD34 or CHOP resulted in various phenotypes upon high levels of ER stress. Our computer simulations suggest the existence of two new feedback loops inside the UPR. First, GADD34 seems to have a positive effect on ATF4 activity, while CHOP inhibits it. We claim that these newly described feedback loops ensure the fine‐tuning of the ATF4‐dependent stress response mechanism of the cell. Key components of the endoplasmic reticulum stress‐activated PERK pathway are ATF4, GADD34, and CHOP. These molecules play important roles in the cellular decision between autophagy and apoptosis. Using systems biological tools, we suggest new relationships (blue lines) that create feedback loops inside the PERK pathway of the unfolded protein response.