Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2016.192 Figure 3 PERK signalling pathways interact with immune response pathways Figure 3 | PERK signalling pathways interact with immune response pathways. In the presence of endoplasmic reticulum (ER) stress and protein misfolding, eukaryotic translation initiation factor 2α (eIF2α) can be phosphorylated by Toll-like receptor (TLR) activation through TIR domain-containing adaptor molecule 1 (TICAM1) and interferon-induced, double-stranded RNA-activated protein kinase (also known as PKR), or by eIF2α kinase 3 (also known as PERK). Translational inhibition leads to rapid decay of inhibitor of nuclear factor-κB (NF-κB) (IκB), which activates NF-κB. Activating transcription factor ATF4 contributes to increased production of IFNβ through DNA damage-inducible transcript protein 3 (CHOP)-mediated upregulation of protein phosphatase 1 regulatory subunit 15A (also known as GADD34). CHOP also mediates synergistic increases in IL-23p19, IL-6 and IL-8 in the context of TLR-stimulated production of these cytokines. ATF5, like ATF4, is translationally upregulated and contributes to inducing gene expression of thioredoxin-interacting protein (TXNIP), which in turn activates the NLRP3 inflammasome. By contrast, TLR stimulation in the absence of ER stress prevents ER-stress-induced eIF2α phosphorylation via eIF2B. BiP, 78 kDa glucose-regulated protein. Navid, F. & Colbert, R. A. (2016) Causes and consequences of endoplasmic reticulum stress in rheumatic disease Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2016.192