Pathogenicity of Misfolded and Dimeric HLA-B27 Molecules

Figure 1

Schematic illustrating the basic outline of the ER stress pathways. The effector molecules of the UPR, the transcription factor ATF6, and the kinases IRE1 and PERK are held in an inactive state via their association with the ER chaperone BiP. On sensing misfolding, BiP dissociates from these effector molecules. This results in ATF6 trafficking to the Golgi where two Golgi resident proteases cleave the ATF6 cytosolic domain which acts as a transcription factor activating folding chaperones. IRE1 oligomerises and autophosphorylates, which can splice the 26-base pair intronic sequence from XBP1 mRNA, which is then religated and encodes for a potent transcription factor. XBP1 induces the production of chaperones and proteins involved in protein folding or degradation. PERK oligomerises and autophosphorylates which in turn phosphorylates the elongation factor 2α that inhibits protein translation. PERK can activate ATF4 and CHOP which can activate apoptosis. Since being reported, little is known about the EOR, which is thought to detect a build-up of proteins within the ER and activate NF-𝜅B, which can target proinflammatory cytokine production.