All eukaryotic cells, including the cells in our body, possess a membrane-enclosed compartment, the endoplasmic reticulum (ER), for the production of proteins that are destined for transport to the cell surface or export into the extracellular fluids. A total of about 10,000 different proteins pass through the ER, including hormones such as insulin, a plethora of other proteins required for cell communication, as well as millions of antibody molecules responsible for our immune defense. Generally, these proteins are subject to intense scrutiny. They are only discharged from the ER when their amino acid chains are properly folded and assembled. For this purpose the ER contains an elaborate molecular machinery of protein folding factors. Imbalances in the production of active species of one or another of the transient ER proteins are the cause of a broad variety of diseases, such as type II diabetes, cystic fibrosis, retinitis pigmentosa, neurodegeneration and certain forms of cancer. Thus, the protein production capacity of the ER must be carefully regulated and adjusted to demands. This year’s awardees of the Shaw Prize in Life Science and Medicine, Kazutoshi Mori and Peter Walter, have discovered the cellular signalling pathway — the so-called Unfolded Protein Response (UPR) — by which protein homeostasis in the ER is regulated. Understanding the UPR not only is of fundamental significance in biology, but also provides new opportunities for the treatment of a wide range of important diseases.
The elucidation of the UPR pathway is one of the most fascinating detective stories of molecular cell biology. It revealed a hitherto unknown mechanism of intracellular stress signalling and regulation of organelle homeostasis. Briefly, when unfolded or incompletely processed proteins accumulate in the ER, their presence must be sensed and a stress signal must be sent to the cell nucleus resulting in the activation of a genetic program that leads to increased production of ER-folding machinery. This is somewhat like opening up additional check-out lanes in a supermarket when customers begin to form queues. The sensor molecule is the protein Ire1, a transmembrane receptor with kinase activity. Ire1, when activated, in turn activates a transcription factor, Hac1. Hac1 then moves into the nucleus to initiate the transcription of genes encoding ER-folding components (molecular chaperones and other factors). These proteins are synthesized in the cytosol and then imported into the ER. As a result, protein flux through the ER is accelerated and the Ire1 sensor is converted back to its inactive state.