ER stress-induced cell death mechanisms

Abstract

The endoplasmic-reticulum (ER) stress response constitutes a cellular process that is triggered by a variety of conditions that disturb folding of proteins in the ER. Eukaryotic cells have developed an evolutionarily conserved adaptive mechanism, the unfolded protein response (UPR), which aims to clear unfolded proteins and restore ER homeostasis. In cases where ER stress cannot be reversed, cellular functions deteriorate, often leading to cell death. Accumulating evidence implicates ER stress-induced cellular dysfunction and cell death as major contributors to many diseases, making modulators of ER stress pathways potentially attractive targets for therapeutics discovery. Here, we summarize recent advances in understanding the diversity of molecular mechanisms that govern ER stress signaling in health and disease. This article is part of a Special Section entitled: Cell Death Pathways.

Keywords: AGE; ALS; AMD; ARE; ASK1; ATF/cAMP response elements; ATF4; ATF6; BAG; BAR; BI-1; Bcl-2 associated athanogene; BiP; CASR; CHOP; CMV; CRE; Cell death mechanisms; DRP-1; Diseases; ER; ER Stress; ER antigen peptide transporter 1; ER stress-response element; ER-assisted degradation; ERAD; ERO1α; ERSE; GADD34; HCV; HFD; HO-1; HSV; IBD; IEC; IP(3)R; IRE1α; JNK; Jun-N-terminal kinase; MEF; MHC; NLRP; NOD-like receptor, (NLR) family pyrin domain-containing; NRF2; PDIA6; PERK; PKC; RIDD; RP; SNP; T2DM; TAP1; TLR; TXNIP; UPR; VEGF; X box-binding protein-1; XBP-1; activating transcription factor 4; activating transcription factor 6; advanced glycated end-products; age-related macular degeneration; amyotropic lateral sclerosis; antioxidant response elements; apoptotic-signaling kinase-1; bax-inhibitor 1; bifunctional apoptosis regulator; binding immunoglobulin protein; calcium-sensing receptor; cytomegalovirus; dynamin-related protein; elF2α; endoplasmic reticulum; endoplasmic reticulum oxidoreductase-1; eukaryotic translation initiation factor; growth arrest and DNA damage-inducible 34; heme oxygenase 1; hepatitis C virus; herpes simplex virus; high fat diet; inflammatory bowel disease; inositol triphosphate receptor; inositol-requiring protein-1; intestinal epithelial cells; major histocompatibility complex; mouse embryonic fibroblast; nuclear erythroid 2 p45-related factor 2; protein disulfide isomerase associated 6; protein kinase C; protein kinase RNA (PKR)-like ER kinase; regulated IRE1-dependent decay of mRNA; retinitis pigmentosa; single nucleotide polymorphism; thioredoxin-interacting protein; toll-like receptor; transcriptional factor C/EBP homologous protein; type 2 diabetes; unfolded protein response; vascular endothelial growth factor.

Figure 1. Endoplasmic reticulum (ER) stress signaling

The ER stress response is mediated by three sensors located at the ER membrane: IRE1α, ATF6 and PERK. Accumulation of unfolded protein recruits BiP to the ER lumen and its dissociation from IRE1α, ATF6 and PERK leads to their activation. Upon dimerization and autophosphorylation, IRE1α splices XBP-1 mRNA, which adjusts the reading frame to allow translation of an active transcriptional factor XBP-1. XBP-1 up-regulates UPR genes encoding ER chaperones and components of the ERAD machinery. IRE1α can also recruit TRAF2 and ASK1, leading to downstream activation of JNK and p38 MAPK. Activated JNK translocates to the mitochondrial membrane and promotes (a) activation of Bim and (b) inhibition of Bcl-2, whereas p38 MAPK phosphorylates and activates CHOP. CHOP can induce transcriptional activation of genes that contribute to cell death, including Ero1α (hyperoxidizes the ER and activates IP₃R) and DR5 (promotes caspase 8-dependent cell death). Bax and Bak can also (a) bind to and activate IRE1α and (b) induce release of Ca²⁺ from the ER. PERK phosphorylates elF2α and attenuates protein translation. However, translation of selected mRNAs is favored under these conditions, including ATF4, which then induces expression of CHOP and GADD34. Activated ATF6 translocates to the Golgi where its cytosolic domain is cleaved by the proteases, S1P and S2P. The cleaved ATF6 fragment forms an active transcriptional factor that mediates expression of several components important for protein folding, degradation, and ER expansion.

Figure 2. Dual function of BI-1 in ER stress and autophagy

BI-1 modulates ER stress and autophagy by independent mechanisms. BI-1 suppresses IRE1α by forming a complex with IRE1α, which then nullifies both its endoribonuclease (XBP-1) and kinase activity (JNK). Via an IP₃R-dependent mechanism, BI-1 also reduces the steady-state levels of ER Ca²⁺, which causes a corresponding decline in mitochondrial Ca²⁺ levels and reduces mitochondria bioenergetics. Reduction in ATP levels (rise in AMP) activates the intracellular energy sensor AMPK, which activates autophagy via effects on Atg1 (Ulk1/Ulk2). BI-1 has also been shown to associate with Bcl-2 to regulate Ca²⁺ homeostasis, which could also indirectly influence autophagy.

Figure 3. Cross-talk of ER stress and autophagy

ER stress can induce autophagy, through at least two UPR pathways, PERK-elF2α and IRE1α. Activated IRE1α can recruit TRAF2 and ASK1, which subsequently activates JNK. JNK-mediated phosphorylation of Bcl-2 releases Beclin-1 from its inhibitory interaction with Bcl-2. Free Beclin-1 associates with other members of the ULK1 complex to promote vesicle nucleation. In parallel, spliced XBP-1 can also trigger transcriptional up-regulation of Beclin-1 expression. The elongation process involves two ubiquitin-like conjugation systems that promote the assembly of Atg5-Atg12-Atg16L complex and the LC3 processing (cleavage and lipidation). Activated PERK can induce autophagy through ATF4-driven transcriptional regulation of Atg12 whereas ATF4-mediated CHOP activation can also transcriptionally induce Atg5. Ca²⁺ release from the ER lumen through the IP₃R can activate CaMKK and subsequently relieves mTOR inhibition on the ULK1 complex.