以表彰他们发现内质网未折叠蛋白反应的贡献；这个反应是一条控制真核细胞内细胞器动态平衡及蛋白质输出质量的信号通道。
2014年度邵逸夫生命科学与医学奖颁予森 和俊(Kazutoshi Mori) 及彼德・瓦尔特 (Peter Walter)，以表彰他们发现内质网未折叠蛋白反应的贡献；这个反应是一条控制真核细胞内细胞器动态平衡及蛋白质输出质量的信号通道。森 和俊是日本京都大学生物物理学教授；彼德・瓦尔特是美国加州大学三藩市分校生物化学与生物物理学教授暨霍华德休斯医学研究所研究员。
我们都应该听过胰岛素和抗体分子。胰岛素负责调节血糖水平；抗体分子由免疫系统制成，负责防御感染。无论胰岛素、抗体分子，还是其他数千种不同的蛋白质，都是由人体细胞内的专门「工厂」制造，然后输出细胞，进入外液。这个「工厂」被称为内质网，是一个膜封闭的亚细胞器，内藏蛋白质组装及包装的分子机器。蛋白质通过内质网，输出细胞外，是要经受严格审查，通过多样的品质控制；就像汽车或电视机生产的品质控制系统一样。如果生产的蛋白质出现错误，或者生产不平衡，会阻塞生产线，引起各种疾病，包括II型糖尿病、囊性纤维化，以至某些癌症。因此，内质网生产蛋白质的能力至为重要，必须仔细规范和调整，以迎合需求。今年的邵逸夫生命科学与 医学奖得奖者是森 和俊及彼德・瓦尔特，他们发现了细胞调节内质网里生产蛋白质的信号通道—即所谓未折叠蛋白反应。
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.
