We previously developed tools through which we can forcibly activate IRE1α at will. Because IRE1α naturally activates through self-association in the ER membrane under ER stress, we can mimic this step by conditionally overproducing the protein from a transgene. In this situation, the transgenic IRE1α protein self-associates by mass action, without requiring upstream ER stress. Thus unlike pleiotropic ER stress-inducing agents that activate all arms of the UPR, our tools allow us to delineate the specific contribution of IRE1α to any UPR-linked physiological process. We decided to employ these tools to study the contribution of IRE1α’s catalytic activities to TXNIP induction (Figure 2C).
