Cell-signaling pathways from the UPR to autophagy and ER stress-induced apoptosis

Cell-signaling pathways from the UPR to autophagy and ER stress-induced apoptosis. Conditions of ER stress where unfolded or misfolded proteins build up cause GRP78 to release three major ER stress sensors on the ER membrane: PERK, ATF6, and IRE1, which are then activated. Upon release from GRP78, IRE1 oligomerizes, autophosphorylates, and processes XBP1 mRNA to produce an active transcription factor, spliced XBP1 (sXBP1). sXBP1 activates stress-inducible genes involved in protein folding and protein degradation, including the genes ER degradation-enhancing alpha-mannosidase-like protein (EDEM), protein disulphide isomerase (PDI), and X box-binding protein 1 (XBP1). Active ATF6 translocates to the nucleus and induces the expression of genes with ER response elements in their promoters, including CHOP and XBP1. Activated PERK dimerizes and autophosphorylates itself. Activated PERK phosphorylates and inactivates eIF2α, which suppresses global cap-dependent mRNA translation, but activates ATF4 translation. ATF4 translocates to the nucleus and induces the transcription of genes for amino acid metabolism, redox reactions, CHOP, and GADD34. These responses reduce the unfolded protein load in the ER by reducing the global protein synthesis, by increasing the folding capacity of the ER and by removing misfolded proteins from the ER. Largely through the two pathways of the UPR, the PERK-eIF2α and IRE1-TRAF2-JNK pathways, ER stressors can induce autophagy (orange arrow). Activation of the PERK-eIF2α axis of the UPR pathways was shown to upregulate Atg12, convert LC3-I to LC3-II, and subsequently facilitate autophagosome formation. Activated IRE1α can recruit tumor-necrosis factor receptor associated factor 2 (TRAF2) and apoptosis-signal regulating kinase (ASK1), subsequently activating JNK. Severe ER stress leads to activation of JNK that downregulates the anti-apoptotic protein Bcl-2 by phosphorylating Bcl-2 on the mitochondrial and ER membrane. JNK-mediated phosphorylation of Bcl-2 releases Beclin1 from its inhibitory interaction with Bcl-2 at ER membrane. Freed Beclin1 induces autophagy through the formation of hVPS34 complexes. The first step of autophagy (induction) is activated by ULK complex composed of ULK1, Atg13, FIP200, and Atg20. The nucleation step is mediated by a complex involving VPS34 (also known as PI3KCIII) with either Beclin1-Atg14L-VPS34-p150 or Beclin1-UVRAG-VPS34-p150. The elongation of the phagophore is mediated by two ubiquitin-like conjugation systems that together promote the assembly of the Atg5-Atg12-Atg16L complex and the processing of LC3. The lipidated form of LC3-I (LC3-II) is attached to both faces of the phagophore membrane. ER stress can induce apoptosis through an intrinsic pathway involving cytochrome c release from mitochondria and caspase activation. Autophagy is also induced via JNK activation that releases Beclin1 from its inhibitory interaction with Bcl-2 at the level of ER, via Bcl-2 phosphorylation. UVRAG, UV radiation resistance associated gene protein; VPS, vacuolar protein sorting; ERAD, ER-associated degradation. Modified and adapted by permission from Nature Publishing Group from Ref. .

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Unfolded protein response to autophagy as a promising druggable target for anticancer therapy. (2012) Dong Hoon Suh, et al. Ann N Y Acad Sci. 2012 Oct;1271(1):20-32. Figure: F1. All organisms Mus musculus Homo sapiens Cricetulus griseus Drosophila melanogaster

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