Crosstalk between the Unfolded Protein Response and NF-κB-Mediated Inflammation in the Progression of Chronic Kidney Disease

Figure 1

Overview of UPR-induced inflammatory gene transcription. The dissociation of GRP78 from the transmembrane transducers, PERK, IRE1α, or ATF6, leads to their activation. PERK activation brought about by autophosphorylation results in the phosphorylation of eIF2α and general translation attenuation reducing the IκB available to bind to NF-κB. Due to IκB’s shorter half-life, more NF-κB is free to enter the nucleus and activate transcription of inflammatory genes. Autophosphorylation of IRE1α causes the cytosolic domain to associate with TRAF2. The IRE1α-TRAF2 complex recruits IKK which phosphorylates IκB resulting in NF-κB activation. This complex recruits protein kinase JNK leading to phosphorylation of transcription factor AP1 as well. Upon activation, ATF6 leaves the ER and undergoes cleavage by site 1 (S1P) and site 2 proteases (S2P) in the Golgi complex. The 50-kilodalton cleavage product (p50) acts as a transcription factor in the nucleus and results in the transcriptional initiation of acute phase inflammatory response genes.