Overview of the Unfolded Protein Response

 As the entry point for the protein secretory pathway, the endoplasmic reticulum (ER) plays an essential role in how cells communicate with each other and with the extracellular environment. The flux of proteins through the ER varies across cell types and conditions, so the ER is dynamic: it constantly adjusts its capacity for folding and processing proteins to balance the cell’s needs, and it physically expands to many times its normal size in developing secretory cells. These tasks are accomplished through a broadly conserved network of signaling pathways called the unfolded protein response (UPR).

 The UPR in mammals is essential for normal development. It is also induced by many diseases that disrupt protein homeostasis, including diabetes, neurodegenerative disorders, and cancer. Since the initial characterization of the UPR in the 1990s, we have learned a lot about how its major signaling branches work. However, the functions of its more recently-discovered branches, including the RIDD pathway described here, have been elusive. Furthermore, the effects of the UPR extend well beyond the ER itself, influencing metabolism, inflammation, and differentiation in ways apparently unrelated to its traditional role in protein folding homeostasis.