The Endoplasmic Reticulum (ER) is responsible for protein synthesis and folding making it the main target for the unfolded protein response (UPR). Cell stress can induce an increase in misfolded proteins that lead to the activation of the UPR through upregulation of sensors, transcription factors and downstream targets to recover homeostasis and control the levels of unfolded proteins in the ER. This adverse outcome pathway (AOP) outlines the way in which inhibition of N-linked glycosylation activates and disrupts the UPR leading to livery injury. It will provide more in depth knowledge on the thresholds involved during the UPR for the maintenance of homeostasis and the induction of the adverse outcome on the target organ of the Liver.
All newly synthesized proteins undergo glycosylation before they are folded in the ER. Any misfolding of proteins is resolved by the ER- associated degradation (ERAD) that recognizes and clears misfolded proteins from the ER. This quality control of protein folding is glycosylation directed. Misfolded proteins that are not N-linked glycosylated fail to be recognized by the ERAD.
The molecular initiating event for this AOP is the inhibition of N-linked glycosylation. This can be achieved through directly inhibiting either the biosynthesis or the processing of N-linked oligosaccharide chains. Enzymes that synthesize N-linked oligosaccharide chain are often targets for inhibition of glycosylation. Unglycosylated misfolded proteins are unable to be recognized or cleared by the ERAD thus leading to key event 1, a buildup of misfolded proteins. This accumulation activates sensors and triggers key event 2: the (UPR).
Whilst the UPR is in place to maintain homeostasis and resolve the buildup of misfolded proteins in the ER. The activation of the UPR coupled with an inability to resolve the buildup of misfolded protein, through compromised ERAD clearance, leads to key event 3: apoptosis of hepatocytes, triggered by UPR downstream target CHOP. This in turn will lead to the adverse outcome: Liver Injury.