Endoplasmic Reticulum Stress in the β-Cell Pathogenesis of Type 2 Diabetes

Figure 1

Activation of cellular responses during ER stress. In the resting state, newly synthesized polypeptides are cotranslationally translocated from the ribosome to the inside of the ER, in which GRP78 (BiP) plays two very important roles. First, GRP78 interacts and stabilizes polypeptides entering the ER and facilitates their proper folding, assembly, and maturation. Second, GRP78 interacts with PERK, IRE1α, and ATF6α, making them stay monomeric and functionally inactive on the membrane. However, these interactions are sensitive to protein folding status and can be easily disrupted by accumulation of misfolded proteins in the ER, resulting in activation of several pathways for protecting cells from accumulation of misfolded proteins: UPR, ERAD, and pQC. The pQC pathway is characterized by substrate-specific inhibition of protein translocation during ER stress, resulting in efficient degradation of mistranslocated proteins in the cytosol. This pathway is physiologically important in terms of controlling protein quantity in damaged ER. Following dissociation of GRP78 from ER stress sensors under ER stress, cells activate the UPR pathways to transfer signals to the nucleus and cytosol. PERK and IRE1α are autophosphorylated and modify their downstream signaling molecules, eIF2α phosphorylation, and Xbp1 mRNA splicing, respectively. Phosphorylated eIF2α attenuates general protein translation in short. In addition, accumulation of phosphorylated eIF2α induces ATF4 expression. Together with ATF4, spliced XBP1 and cytosolic fragments of ATF6α (p50) transcriptionally activate various UPR genes involved in either adaptation or apoptosis during ER stress.