Cells expend considerable resources to maintain secretory homeostasis when ER stress levels fall within containable limits. Paradoxically when ER stress levels rise above critical thresholds, cells actively commit to programmed cell death. Robust signaling networks may force cells to make such a binary choice. We predicted the existence of signaling proteins that mediate destructive responses to catastrophic ER stress, and sought to discover such proteins using unbiased screens. Using a strategy to identify translational targets of the UPR (which was historically described and studied as a transcriptional pathway), we identified thioredoxin-interacting protein (TXNIP) as a critical mediator of cell death in response to catastrophic ER stress—a process we refer to as a terminal UPR.
