Expression of transgenic WT IRE1α (using doxycycline—Dox) causes the protein to spontaneously autophosphorylate as it accumulates (Figure 2E); this leads to complete conversion of cellular XBP1 mRNA to the spliced form (Figure S4C), as occurs under ER stress (Figure S2A)(Han et al., 2009). Activation of WT IRE1α through this maneuver is sufficient to induce TXNIP mRNA (Figure 2D and S4E) and protein (Figure 2F).