Figure 3.

Unfolded protein response. Mammalian unfolded protein response (UPR) is a tripartite response involving three proximal sensors: activating factor (ATF) 6, RNA-dependent protein kinase-like ER-resident kinase (PERK) and inositol-requiring enzyme 1 (IRE1). Left: ATF6 is sequestered in an inactive state by the molecular chaperone the immunoglobulin heavy-chain binding protein (BiP). Unfolded/malfolded proteins “distract” BiP from ATF6. ATF6 de-oligomerizes and migrates to the Golgi, where the monomer is cleaved by site-1 and site-2 proteases (red scissor) into an active transcription factor. The truncated N-terminal ATF6 is translocated to the nucleus where it transactivates UPR genes harboring an ERSE in their promoters e.g., BiP, glucose-regulated protein 94 (GRP94), P58^IPK. Middle: PERK is sequestered in an inactive state by BiP. Unfolded/malfolded proteins “distract” BiP from PERK, allowing its oligomerization and auto-phosphorylation (red asterisk). The activated PERK then phosphorylates its substrate, the alpha subunit of the eukaryotic initiation factor 2 (eIF2α) (red asterisk) to inhibit global protein synthesis. Paradoxically, translation of ATF4 is upregulated to drive transcription of UPR genes with an ATF4 element in their promoters e.g., the CCAAT/enhancer-binding protein-homologous protein (CHOP). CHOP is a pro-apoptotic transcription factor, as it transactivates a number of apoptotic genes and downregulates the anti-apoptotic Bcl-2. ATF4 co-operates with CHOP to transactivate ATF3 and the growth arrest and DNA damage-inducible protein 34 (GADD34). GADD34 is the regulatory subunit of the protein phosphatase 1 (PP1). It recruits PP1 to dephosphorylate eIF2α (red blunt arrow), thus establishing a negative feedback loop. Right: Analogous to yeast, it is thought that IRE1 is activated by direct binding of unfolded/malfolded proteins to its luminal domain and BiP plays a regulatory role. IRE1 possesses endoribonuclease and kinase activity. The endoribonuclease activity mediates unconventional splicing of XBP1 (purple scissor) (usXBP1, unspliced XBP1 mRNA; sXBP1, spliced XBP1 mRNA). The sXBP1 mRNA is translated into an active transcription factor sXBP1 to transactivate genes with ERSE or UPRE in their promoters. XBP1 upregulation of UPR genes such as BiP and ERAD genes such as EDEM and ERdj4 provides a link between UPR and ERAD. XBP1 provides a link between the IRE1 and PERK pathways by upregulating P58^IPK, an inhibitor of PERK. XBP1 also orchestrates lipogenesis and ER expansion. The other endoribonuclease activity of IRE1 cleaves the ribosomal RNA (rRNA) (purple scissor) and mediates regulated IRE1-dependent decay (RIDD) to cleave a subset of mRNAs (purple scissor) to inhibit protein synthesis. The kinase activity of IRE1 plays a role in cell death/survival. Phosphorylated IRE1 (red asterisk) recruits the adaptor protein tumor necrosis factor receptor-associated factor 2 (TRAF2) to activate a cascade of phosphorylation culminating in pro-apoptotic Jun amino-terminal kinase (JNK) (red asterisk) and pro-survival c-Jun (red asterisk). Red asterisk, activation by phosphorylation.