Intracellular Signaling by the Unfolded Protein Response

Abstract

The unfolded protein response (UPR) is an intracellular signaling pathway that is activated by the accumulation of unfolded proteins in the endoplasmic reticulum (ER). UPR activation triggers an extensive transcriptional response, which adjusts the ER protein folding capacity according to need. As such, the UPR constitutes a paradigm of an intracellular control mechanism that adjusts organelle abundance in response to environmental or developmental clues. The pathway involves activation of ER unfolded protein sensors that operate in parallel circuitries to transmit information across the ER membrane, activating a set of downstream transcription factors by mechanisms that are unusual yet rudimentarily conserved in all eukaryotes. Recent results shed light on the mechanisms by which unfolded proteins are sensed in the ER and by which the unfolded protein signals are relayed and integrated to reestablish homeostasis in the cell's protein folding capacity or—if this cannot be achieved—commit cells to apoptosis.