Figure 3.

Endoplasmic reticulum stress-associated NFκB activation is shown. ER stress-induced activation of IRE1α kinase activity recruits adaptor protein tumor-necrosis factor-α (TNF-α) receptor-associated factor 2 (TRAF2), which further recruits c-Jun N-terminal kinase (JNK) activating several transcription factors and many apoptosis signaling proteins. JNK induces the expression of inflammatory genes by phosphorylating the transcription factor activator protein 1 (AP-1), which is a dimer of monomers from various protein families forming different combinations of AP-1. They induce inflammation via promoting transcription of genes for cytokines, chemokines, and other proinflammatory molecules. TRAF2 associates with IκB kinase (IKK) activating NF-κB by promoting degradation of IκBα resulting in NF-κB nuclear translocation. PERK branch of UPR also can potentially induce NF-κB not by IκBα phosphorylation or degradation but essentially by its eIF2α-mediated attenuation of translation; successively inhibiting the synthesis of IκBα. Subtilase cytotoxin from Shiga strain of E. coli makes a specific single site cleavage in GRP78, therefore capable of eliciting ER stress response pathways. CREBH and ATF6 may dimerize and synergistically activate transcription of major APR genes inducing a systemic inflammatory response in specific cells.