Abstract:

A healthy proteome is crucial for cellular function. Cells therefore mount various adaptive mechanisms to respond to and correct protein-folding defects. In the endoplasmic reticulum (ER), where transmembrane and secretory proteins are folded and assembled, protein-folding homeostasis is maintained by a network of signaling pathways, collectively called the unfolded protein response (UPR). Protein folding perturbations in the ER activate UPR sensor/transducers to restore homeostasis in the organelle. IRE1 is the most evolutionarily conserved UPR sensor. Using structural biology and cell biology approaches, we recently dissected how mammalian IRE1 senses protein folding perturbations in the ER lumen. Moreover, using systems level methods, we revealed that IRE1 cross-talks with co-translational targeting machinery to adjust protein-folding load of the organelle. We anticipate that the mechanistic principles derived from our work will help to reveal how IRE1 dysregulation contributes to pathologies in diseases such as cancer and neurodegeneration.