Endocrine Abstracts

The endoplasmic reticulum (ER) is a cellular compartment specialized for chaperone-assisted folding and post-translational modification of nascent polypeptides. Disruption of ER homeostasis leads to accumulation of unfolded protein and activation of the unfolded protein response (UPR). The UPR emanates from the ER through activation of three transmembrane sensors, IRE1, PERK, and ATF6. IRE1 is a protein kinase / endoribonuclease that, upon activation, initiates a splicing reaction that removes a 26b intron within the XBP1 mRNA. Spliced XBP1 mRNA produces a potent basic leucine zipper (bZiP)-containing transcription factor of the ATF/CREB family that activates UPR gene transcription. Activation of PERK by ER stress leads to inhibition of translation initiation through phosphorylation of eukaryotic initiation factor 2 (eIF2) on the alpha subunit. Paradoxically, there are several mRNAs that require eIF2α phosphorylation for efficient translation, ie. ATF4 mRNA. ATF4 encodes a transcription factor required to activate genes involved in amino acid biosynthesis and transport, anti-oxidative stress responses, and proapoptotic functions, such as CHOP. Finally, ATF6 is an ER transmembrane protein that contains a bZiP domain in the cytosolic domain and a stress-sensing domain in the ER lumen. Upon accumulation of unfolded proteins in the ER lumen, ATF6 transits to the Golgi compartment for cleavage by the proteases S1P and S2P to generate the cytosolic fragment which traffics to the nucleus to activate transcription of a subset of UPR target genes. Recent studies demonstrate that the UPR plays important fundamental roles in the etiology of insulin resistance and type 2 diabetes. Studies will summarize that the unique and essential features of the cellular response to ER stress and how ER stress is intimately coupled with oxidative stress and beta cell failure. Glucose-regulated insulin production in pancreatic beta cells requires an intact PERK/eIF2a subpathway to prevent oxidative stress.