The unfolded protein response (UPR) is a eukaryotic cell process that addresses ER stress. UPR is initiated by three ER-localized sensors: PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 alpha (IRE1 alpha). UPR-downstream signaling is modulated by the ATF6 and IRE1-XBP1 pathways. UPR has the following important functions: inhibit protein translation to restore normal cell function; increase protein folding-involved chaperone production; and activate misfolded protein ubiquitination (for both targeting and degradation). If ER-stress is not appropriately addressed, the UPR system triggers a fail-safe of apoptosis. The IRE1 alpha protein is a single-pass, type I membrane protein within the ER that functions as a sensor of unfolded ER proteins. It is ubiquitously expressed, with highest levels notably in the pancreas. IRE1 alpha autophosphorylates and under ER stress conditions, is ADP-ribosylated by the protein PARP16. This post-translational modification dually increases both the intrinsic serine-threonine kinase and endoribonuclease activities of IRE1 alpha. IRE1 alpha inactivation in mice results in widespread developmental defects and sometimes intra-gestational embryonic lethality. Lipson et al employed the IRE1 alpha antibody in their signaling pathway mapping on insulin biosynthesis in pancreatic beta cells1. Luo’s group from Yale University performed IRE1 alpha antibody immunoprecipitation and immunoblotting in their targeted assessment of AIP1’s role in the stress response2. Koh et published their results in Nature Communications on Tribbles 3 contribution to stress-induced insulin resistance in skeletal muscle3. They relied upon the IRE1 alpha antibody to extend Tribbles 3 function to skeletal muscle in addition to previously identified tissues. A recent study from Cai’s lab used the IRE1 alpha antibody in their work on chronic intermittent hypoxia (CIH)4. Their findings identify CIH-induced injury and subsequent apoptosis as an underlying mechanism of cognitive dysfunction in sleep apnea. Assessments on the effects of ER stress on renal fibrosis are somewhat divided, but Chiang’s group from the National Taiwan University have data suggesting that a positive in vivo correlation5. Their studies with the IRE1 alpha antibody indicate that renal integrity and reversal of tubular damage can be achieved through the inhibition of ER stress-related apoptosis.
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