Figure 5. The UPR as an inflammatory nidus.
a | Inositol-requiring enzyme 1α (IRE1α) activation and subsequent splicing of X-box binding protein 1 (Xbp1) produces the transcription factor XBP1s that directly binds the promoters of tumour necrosis factor (Tnf) and interleukin-6 (Il6). b | Regulated IRE1α-dependent decay (RIDD)-dependent degradation of miR-17, which in unstressed conditions represses thioredoxin-interacting protein (Txnip), allows for increased TXNIP levels and NLRP3 inflammasome activation with upregulation of IL-1β. In addition, Txnip can be induced through the PKR-like ER kinase (PERK)-activating transcription factor 5 (ATF5) pathway to induce inflammasome activation. c | Activated IRE1α forms a complex with TNF receptor-associated factor 2 (TRAF2) to induce phosphorylation of Jun N-terminal kinase (JNK) and upregulation of pro-inflammatory genes through activated activator protein 1 (AP1). d | In addition, the IRE1α –TRAF2 complex recruits IκB kinase (IKK), and subsequent phosphorylation of IκB leads to its degradation, which releases nuclear factor-κB (NF-κB) for nuclear translocation. e | Translation attenuation by PERK-dependent phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) results in decreased translation of both IκB and NF-κB. However, owing to the shorter half-life of IκB, the net result is an increased NF-κB to IκB ratio, which promotes inflammation. f | ATF4 directly binds the Il6 promoter. g | ATF6α induces NF-κB signalling via AKT phosphorylation. h,i | Site 1 protease (S1P)- and S2P–mediated cleavage of ATF6α and CREBH allows their cleavage fragments to translocate to the nucleus and induce genes of the acute phase response (APR). BiP, binding immunoglobulin protein.