Chaperone foldase systems in the mammalian ER. The relationship between the GRP94 and calnexin/calreticulin chaperone is not established. Abbreviations: Glc—d-glucose, P_i—inorganic phosphate (HPO₄²⁻)

Disulfide bond formation in the mammalian ER. (a) Human PDIs. Rectangles represent thioredoxin-like domains. Black rectangles represent transmembrane domains, rectangles labeled ‘J’ DnaJ domains, and labeled ‘FAD’ sequences involved in FAD binding. Catalytic site sequences and known ER retention signals are shown in the single letter amino acid code. (b) Human ERO and Erv-like proteins. QSOX1a and QSOX1b are products of alternative splicing. (c) Schematic of disulfide bind formation and isomerization reactions catalyzed by PDIs. Reprinted from (Schröder 2008b)

Principal signal transduction pathways in the mammalian UPR. Abbreviations: C-3, caspase 3; C-9, caspase 9; C-12, caspase 12; pC-12, procaspase 12. Reprinted in modified form from Fig. 6 published in Schröder (2008a), copyright 2007, Birkhäuser Basel, with kind permission of Springer Science and Business

Induction of apoptosis in the UPR. (a) Principal pathways according to the direct binding and the displacement models. In the direct binding model (left) proapoptotic BCL-2 proteins such as BIM associate with and activate BAK/BAX, leading to BAK/BAX oligomerization and insertion into the mitochondrial membrane, cytochrome c efflux, and activation of caspase 9. In the displacement model antiapoptotic BCL-2 proteins associate with and inactivate BAK/BAX. Proapoptotic BCL-2 family proteins, whose cytosolic concentration increases in response to intracellular damage, bind to and sequester antiapoptotic BCL-2 proteins from BAK/BAX, leading to BAK/BAX activation (Häcker and Weber 2007; Karst and Li 2007). Reprinted from Fig. 8 published in Schröder (2008a), copyright 2007, Birkhäuser Basel, with kind permission of Springer Science and Business. (b) Anti- and proapoptotic BCL-2 proteins and their regulation in the ER stress response. BH1, BH2, BH3, BH4, and transmembrane (TM) domains are represented by rectangles

Recognition of N-linked oligosaccharides as a marker for protein folding status (Lederkremer and Glickman 2005, Moremen and Molinari 2006). Oligosaccharyltransferase transfers the oligosaccharide Glc₃Man₉GlcNAc₂ (left, ▲—d-glucose, ○—d-mannose, □—2-N-acetyl-d-glucosamine) onto a newly synthesized polypeptide chain. α-glucosidases I and II (α-Glc I, α-Glc II) remove the two terminal d-glucose moieties. The monoglucosylated form is recognized by calnexin, calreticulin, or calmegin and retained in the ER. Upon removal of the terminal d-glucose moiety by α-glucosidase II, the protein is released from the lectin chaperone, but if still unfolded is reglucosylated by UDP-glucose:glycoprotein glucosyl transferase (UGGT). Removal of d-mannoses B and C converts the oligosaccharide into a poorer substrate for UGGT and α-glucosidase II and decreases the affinity of the oligosaccharide for calnexin and calreticulin and indirectly promotes export to the Golgi complex via recognition of oligosaccharides containing α(1,2)-linked d-mannose residues by export lectin receptors such as ERGIC-53. Trimming of d-mannose A removes the d-glucose acceptor from the oligosaccharide, efficiently blocks the reglucosylation reaction, inhibits the interaction with ERGIC-53, and triggers retrotranslocation and proteasomal degradation of slowly folding proteins. The demannosylation reactions are slower than the deglucosylation reactions. α(1,2)-ER mannosidase I preferentially removes d-mannose B, and more slowly the other d-mannose moieties. Golgi resident mannosidases exhibit specificity for d-mannoses A, C, and D and may be involved in trimming of the α(1,2)-linked d-mannose residues. Reprinted from Fig. 3 published in Schröder (2008a), copyright 2007, Birkhäuser Basel, with kind permission of Springer Science and Business

ERAD (a) and autophagy (b). Formation of the phagophore is inhibited by TOR signaling and stimulated by a class III, wortmannin and 3-methyladenine sensitive PI3K. Abbreviations: PP_i—pyrophosphate, Ub—ubiquitin. Numbers in circles represent ATG proteins. Reprinted in modified form from Fig. 2 published in Schröder (2008a), copyright 2007, Birkhäuser Basel, with kind permission of Springer Science and Business

Signal transduction by PERK. Abbreviation: m⁷G—7-methylguanosine. Reprinted from Current Molecular Medicine, copyright 2006, with permission from Bentham Science Publishers

Autocrine TNF signaling. Membrane-bound TNF (mTNF) is released from the plasma membrane by the protease TACE. Soluble (sTNF) or membrane-anchored TNF interacts with receptors of the TNF receptor (TNF-R) family. Interaction with death domain (DD)-containing receptors such as FAS, TRAIL-R1, and TRAIL-R2 recruits FADD and caspase-8 to the receptor and activates caspase-8. Other DD-containing receptors such as TNF-R1, DR3, and DR6 activate caspase-8 in a complex with TRADD. Conformational changes in the cytosolic domains of TNF-R1 induced by TNF binding release the inhibitory protein SODD from the cytosolic effector domains of the receptor. Binding of TRAF2 to the receptor TRADD complex either recruits cIAP to inhibit caspase-8 activation, or recruits IKK kinase and MAPKKKs such as ASK1 to activate NF-κB and the MAPK p38 and JNK. TRAF2-associated proteins such as RIP contribute to modulation of the outcome of TNF-R1 signaling. TNF-Rs with a cytosolic TRAF-interacting motif (TIM) domain directly associate with TRAF2 to activate IKK, p38, and JNK. TNF-R2 is preferentially activated by mTNF. Decoy receptors lack cytosolic effector domains and inhibit TNF signaling (Dempsey et al. 2003; Wajant and Scheurich 2001). Abbreviation: DED—Death effector domain