for their discovery of the Unfolded Protein Response of the endoplasmic reticulum, a cell signalling pathway that controls organelle homeostasis and quality of protein export in eukaryotic cells.
The Shaw Prize in Life Science and Medicine 2014 is awarded to Kazutoshi Mori, Professor of Biophysics at Kyoto University, and Peter Walter, Professor of Biochemistry and Biophysics at the University of California, San Francisco and Howard Hughes Medical Institute Investigator, for their discovery of the Unfolded Protein Response of the endoplasmic reticulum, a cell signalling pathway that controls organelle homeostasis and quality of protein export in eukaryotic cells.
We have all heard of insulin, the regulator of blood sugar level, or of the antibody molecules made by the immune system as a defense against infection. Along with thousands of other proteins, these molecules are produced by cells of our body in a specialized protein factory for export into the extracellular fluids. This factory is called the endoplasmic reticulum (ER), a membrane-enclosed compartment within the cell that is filled with molecular machinery for protein assembly and packaging. Proteins that pass through the ER on their way out are subject to intense scrutiny. They are only discharged after clearing an extensive quality control system, similar to the construction of cars or TV sets. Mistakes or imbalances in production can jam the assembly line and are the cause of a broad variety of diseases, including type II diabetes, cystic fibrosis 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 cells regulate protein production in the ER.
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.
Kazutoshi Mori was born in 1958 in Kurashiki, Okayama, Japan and is currently Professor of Biophysics in the Graduate School of Science at Kyoto University. He graduated from the Faculty of Pharmaceutical Sciences at Kyoto University in 1981, obtained his PhD there and was appointed Assistant Professor at Gifu Pharmaceutical University in 1985. From 1989 to 1993, he was a postdoctoral fellow in the University of Texas. He was Research Manager at the HSP (Heat Shock Protein) Research Institute in Kyoto from 1993 to 1998, and has been a member of the faculty of Kyoto University since 1999.
Peter Walter was born in 1954 in Berlin, Germany and is currently Professor of Biochemistry and Biophysics at the University of California, San Francisco and an Investigator of the Howard Hughes Medical Institute, USA. He graduated from the Free University of Berlin in 1976, received his MS degree in Organic Chemistry from Vanderbilt University in 1977, and obtained his PhD in Biochemistry at The Rockefeller University in 1981. He was Assistant Professor at The Rockefeller University in 1982, and joined the University of California, San Francisco in 1983. He is a member of the US National Academy of Sciences, and the German Academy of Natural Scientists Leopoldina.
