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.

Both awardees contributed equally to this important discovery. In 1993, Peter Walter and Kazutoshi Mori, working independently, discovered the Ire1 kinase (termed ERN1 by Mori) and proposed that Ire1 transmits signals from the ER to the nucleus (Cell 73, 1197–206, 1993; Cell 74, 743–56, 1993). In 1996 Mori took the next step and discovered the protein Hac1, the nuclear transcription factor required for transcription of ER-folding components (Genes Cells 1, 803–17, 1996). Two months later, Walter independently described Hac1 and made the surprising discovery that the HAC1 message undergoes splicing upon activation of the UPR (Cell 87, 391–04, 1996). He showed that the Ire1 kinase is also an endoribonuclease specific for HAC1 mRNA (Cell 90, 1031–39, 1997). Mori confirmed HAC1 splicing one month later (Mol Biol Cell 8, 1845–62, 1997). Next Walter reconstituted HAC1 splicing in vitro and showed that the process resembles pre-tRNA splicing (EMBO J 18, 3119–32, 1999). Also in 1999 Mori discovered the mammalian transcription factor ATF6 (all previous discoveries were made in yeast cells), which is made as an ER membrane protein. He found that ATF6 is a second ER-resident effector of the UPR (in higher eukaryotes and mammals) and that it is proteolytically severed from the ER upon UPR induction (Mol Biol Cell 10, 3787–99, 1999). In 2001 Mori independently (Cell 107, 881–891, 2001) and together with Randall Kaufman (Cell 107, 893–903, 2001) discovered XBP1 as the mammalian HAC1 ortholog. The next big step forward followed in 2005 when Walter together with his collaborator Stroud reported the crystal structure of the ER luminal domain of Ire1. They suggested that the protein forms a MHC1-like peptide binding groove, which may bind misfolded proteins directly.

The Selection Committee carefully considered the contribution by other scientists to the elucidation of the UPR pathway and concluded unanimously that Mori and Walter have by far made the most seminal discoveries. Walter and Mori also shared the Canadian Gairdner International Award and the American Wiley Prize.

Life Science and Medicine Selection Committee
The Shaw Prize

24 September 2014   Hong Kong