TXNIP gene regulation is robustly wired into the terminal UPR. TXNIP up-regulation occurs rapidly when cells experience ER stress acutely at irremediable levels. Alternatively, chronic low-level ER stress in β-cells (e.g. due to Akita proinsulin) also increases TXNIP basal levels. While we discovered TXNIP as a translational target, its mRNA levels also climb greater than tenfold within 2 hours in a terminal UPR. Contemporaneously, TXNIP mRNA becomes loaded onto poly-ribosomes to begin translation. Intriguingly, the new steady-state level of TXNIP mRNA under ER stress is achieved through mRNA stabilization combined with de novo transcription. We found that TXNIP mRNA is inherently unstable, reminiscent of CHOP mRNA, which encodes a pro-apoptotic UPR transcription factor (Rutkowski et al., 2006), Furthermore, through a regulated event, TXNIP mRNA becomes stabilized under ER stress. Master regulatory proteins controlling switching into different cell states are often encoded by short-lived mRNAs, thus ensuring rapid interconversion of cell states. It is conceivable that other master regulators of the terminal UPR are encoded by short-lived mRNAs.
