Figure 1.

Pathways of protein misfolding that lead to cell death. Nascent unfolded polypeptides enter the endoplasmic reticulum (ER) and interact with chaperones and catalysts of protein folding to mature into compact, thermodynamically favourable structures. Failure of this process results in persistence of misfolded polypeptide–chaperone complexes or extraction of soluble, misfolded protein from the ER and through ER-associated protein degradation (ERAD). The formation of insoluble protein aggregates requires clearance by autophagy. ER stress stimuli impair polypeptide folding and induce adaptive increases in chaperones and catalysts within the ER lumen through unfolded protein response (UPR) sensor activation. Chronic or overwhelming stimuli elicit a number of apoptotic signals including oxidative stress, cJun-N-terminal kinase (JNK) activation, CHOP expression, cleavage of caspase 12 and activation of the intrinsic mitochondrial-dependent cell death pathway. Physiological stimuli that can activate the UPR in the β-cell include expression of misfolded proinsulin or islet amyloid polypeptide (IAPP), oxidative stress [reactive oxygen species (ROS)] and increases in the extracellular concentrations of glucose, fatty acids or cytokines.