Molecules and Cells

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Fig. 2.

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Fig. 2. ER-resident proteins IRE1, PERK, and ATF6 sense ER stress and deliver distinct signals from the ER to the cytosol. Under normal conditions, Grp78 binds to the ER luminal domains of sensor proteins and inhibits their activation. However, Grp78 dissociates from the sensors in response to ER stress and binds to unfolded proteins, leading to activation of the sensors. (A) IRE1 pathway; IRE1 has Ser/Thr kinase and RNase domain in the cytoplasmic region, and ER stress induces IRE1 oligomerization and autophosphorylation of the kinase domain. The RNase domain of activated IRE1 performs unconventional splicing and cleaves 26 intronic nucleotides from XBP1 mRNA in mammalian cells. This splicing induces a translational frame-shift, and the truncated XBP1 mRNA encodes XBP1s, which contains a new carboxyl terminus. As a transcription factor, XBP1s activates UPR-related genes including ER chaperones, ERAD components, and lipid-biosynthetic enzymes. (B) PERK pathway; PERK is a protein Ser/Thr kinase that undergoes oligomerization and autophosphorylation of the kinase domain under conditions of ER stress. Activated PERK phosphorylates eIF2α at serine 51, resulting in general inhibition of protein translation. However, phosphorylated eIF2α selectively increases the translation of ATF4, which upregulates CHOP and GADD34 mRNA. As a negative feedback mechanism, GADD34 promotes dephosphorylation of eIF2α to restore protein synthesis following elimination of ER stress. However, failure to alleviate ER stress leads to CHOP-mediated apoptosis. (C) ATF6 pathway; ATF6 has a bZIP domain in the cytosol and translocates from the ER to the Golgi apparatus under ER stress. ATF6 is then cleaved by the proteases S1P and S2P to produce the aminoterminus of ATF6 (ATF6-N), which then migrates to the nucleus and upregulates target genes encoding ER chaperones, ERAD components, and XBP1. RNase, endoribonuclease; XBP1, X-box binding protein 1; eIF2α, α-subunit of eukaryotic translation initiation factor 2; ATF4, activating transcription factor 4; CHOP, C/EBP homologous protein; GADD34, growth arrest and DNA damage-inducible protein 34; S1P, site-1 protease.
Mol. Cells 2018;41:705~716
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