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.

The elucidation of the UPR pathway is one of the most fascinating detective stories of modern biology. It revealed a hitherto unknown mechanism of cellular stress signalling and regulation. Kazutoshi Mori and Peter Walter, working independently at the University of Texas Medical Center in Dallas and the University of California, San Francisco, made their first breakthrough in 1993 by discovering Ire1, the central signalling molecule used for communicating the status of the ER production line (Mori soon after moved to the University of Kyoto). Briefly, when unfolded or incompletely processed proteins accumulate in the ER, their presence is sensed by Ire1 and a stress signal is sent across the ER membrane. Ire1 in turn activates a transcription factor, HAC1, which then moves into the cell nucleus to initiate the transcription of genes encoding the tools needed to repair the unfolded proteins that are stuck in the ER. These factors are synthesized in the cytosol of the cell and then imported into the ER. As a result, normal protein production in the ER is restored and the Ire1 sensor is switched off.

The fundamental mechanisms uncovered by Mori and Walter form the basis for understanding and treating a wide range of important diseases such as cancer, metabolic disorders including obesity, diabetes, fatty liver and dyslipidemia, a number of neurodegenerative diseases, and inflammatory diseases. Signalling components of the UPR are emerging as potential targets for intervention and treatment of these human diseases. For example, finding drugs that activate the UPR may be helpful in the treatment of type II diabetes. In contrast, inhibition of the UPR is considered promising in the therapy of certain forms of leukemia in which white blood cells produce overshooting amounts of antibody molecules.

Life Science and Medicine Selection Committee
The Shaw Prize

27 May 2014   Hong Kong