Fig. 3: The regulatory mechanism of SESN2 during ER stress.
From: Sestrin2: multifaceted functions, molecular basis, and its implications in liver diseases
ER stress agonists, thapsigargin, brefeldin A, and tunicamycin, can excite ER stress via inducing GRP78 dissociation and liberation of IRE1α, PERK, and ATF6. IRE1α phosphorylates and forms a dimer, cleaving XBP1 mRNA into an active form XBP1s. ATF6 when liberated translocates into Golgi and is lysed to ATF6p50 by S1P/S2P. Both XBP1 and ATF6p50 as transcription factors can up-regulate the transcription of downstream genes including XBP1, GRP78, GRP94, and SESN2, which promotes protein folding and misfolded protein degradation, and relieves ER stress. Induced SESN2 can arrest protein synthesis and enhance autophagy via AMPK-mTORC1 pathway and reduces oxidative damage via Nrf2. PERK phosphorylates and dimerizes, phosphorylating downstream elF2α and subsequently promoting the transcriptional activity of ATF4. ATF4 can initiate the transcription of CHOP, enhancing protein synthesis, apoptosis, and pyroptosis. ATF4 can also induce SESN2 expression.
