IRE1: Apoptosis, Autophagy and ER Stress Response

IRE1 resides in the endoplasmic reticulum (ER) as a transmembrane protein with both serine-threonine kinase and endoribonuclease activities. It acts as an unfolded protein response (UPR) sensor through XBP1 transcriptional activation and has been found to have many physiological functions due to the fundamental importance of protein folding. Lipson’s group used the IRE1 antibody in pancreatic beta cells to demonstrate that IRE1 phosphorylation in response to high glucose conditions is coupled to insulin biosynthesis (1). In liver cells, IRE1 antibody was used to show demonstrate that cannabidiol (CBD)-induced apoptosis activates the ER stress response including the IRE1 pathway and other pro-apoptotic pathways including c-Jun N-terminal kinase (JNK) (2). This signaling was found to be specific for hepatic stellate cells (HSC), making them more susceptible to CBD’s effects and therefore a potential therapeutic target for treating liver fibrosis. Further connections between IRE1 and JNK signaling were made by Luo, et. al. in knockout mice (3). The IRE1 antibody allowed them to establish that the ASK1-interacting protein (AIP1) transduced the ER stress response, expanding AIP1’s role outside of tumor necrosis factor (TNF)-induced signaling. IRE1 antibody was also employed in in-depth analysis of the Bax inhibitor 1 (Bl-1) protein as a “stress integrator” that modulates autophagy and other homeostatic processes in both murine and drosophila systems (4). Researchers in Amsterdam studying Alzheimer’s disease (AD) and the phosphorylated tau (p-Tau) protein used IRE1 antibody in immunohistochemical studies to directly link elevated UPR activity with neuronal pathological degeneration in a beta Amyloid deposit-independent manner (5).