Fig 2: Cell apoptosis under ER stress. PERK-eIF2a-ATF4-CHOP, IRE1-XBP1-TRAF2-JNK are the major signaling pathways that contribute to ERS-induced autophagy. Persistent and severe ERS can induce cell apoptosis though PERK and IRE1 signaling. ATF4 is a key proapoptotic factor. CHOP downregulates anti-apoptotic Bcl-2 expression to promote apoptosis. IRE1 inhibits expression of the antiapoptotic protein Bcl-1 and activates proapoptotic proteins Bim through the IRE1-TRAF2-ASK1-JNK pathway. ASK1, apoptosis signal-regulating kinase 1; ATF4, activating transcription factor 4; Bim, Bcl-2-like protein 11; Bip, immunoglobulin heavy chain binding protein; CHOP, C/EBP-homologous protein; eIF2a, eukaryotic initiation factor 2a; ER, endoplasmic reticulum; GADD34, growth arrest and DNA damage-inducible protein 34; IRE1, inositol-requiring enzyme 1; JNK, c-Jun N-terminal kinase; P, phosphate; PERK, protein kinase R-like ER kinase; TRAF2, tumor necrosis factor receptor associated factor 2; XBP1s, X box-binding protein-1s.