Secretory pathway and mechanisms of β-cell defense against protein misfolding. The major β-cell secretory proteins, insulin
and IAPP, are synthesized and folded in the ER and then processed within the secretory pathway (Golgi and secretory vesicles).
Misfolded proteins are targeted to the ER-associated degradation, also known as ubiquitin-proteasome system (UPS), that involves
ubiquitination of the targeted proteins, their deubiquitination by enzymes such as UCH-L1, and subsequent degradation by the
proteasome. If the ubiquitin-proteasome system fails or if protein aggregates form, an alternative pathway of protein clearance
becomes available: the autophagy pathway in which membranes surround the material to be degraded (ubiquitinated proteins and
protein aggregates but also damaged organelles and aged vesicles) to form autophagosomes that fuse with lysosomes to allow
degradation of their content.