Figure 3. Proposed models for UPR-mediated JNK and NF-κB activation.

In response to ER stress, PERK mediates a general repression of mRNA translation by phosphorylating eIF2α. Because IκB has a shorter half-life than NF-κB, PERK-mediated translational attenuation shifts the ratio of IκB to NF-κB, thereby freeing NF-κB to translocate to the nucleus. In addition, in response to ER stress, the cytoplasmic domain of phosphorylated IRE1α can recruit tumour-necrosis factor-α (TNF-α)-receptor-associated factor 2 (TRAF2). The IRE1α–TRAF2 complex interacts with JNK and/or IκB kinase (IKK), activating these protein kinases. Activated JNK phosphorylates the transcription factor activator protein 1 (AP1). Activated IKK phosphorylates IκB, initiating the degradation of IκB and thereby leading to NF-κB activation. Activated NF-κB and AP1 then migrate to the nucleus, where they induce the transcription of genes involved in the inflammatory response.