以表彰他們發現內質網未折疊蛋白反應的貢獻；這個反應是一條控制真核細胞內細胞器動態平衡及蛋白質輸出質量的信號通道。
2014年度邵逸夫生命科學與醫學獎頒予森 和俊(Kazutoshi Mori) 及彼德・瓦爾特 (Peter Walter)，以表彰他們發現內質網未折疊蛋白反應的貢獻；這個反應是一條控制真核細胞內細胞器動態平衡及蛋白質輸出質量的信號通道。森 和俊是日本京都大學生物物理學教授；彼德・瓦爾特是美國加州大學三藩市分校生物化學與生物物理學教授暨霍華德休斯醫學研究所研究員。
我們都應該聽過胰島素和抗體分子。胰島素負責調節血糖水平；抗體分子由免疫系統製成，負責防禦感染。無論胰島素、抗體分子，還是其他數千種不同的蛋白質，都是由人體細胞內的專門「工廠」製造，然後輸出細胞，進入外液。這個「工廠」被稱為內質網，是一個膜封閉的亞细胞器，內藏蛋白質組裝及包裝的分子機器。蛋白質通過內質網，輸出細胞外，是要經受嚴格審查，通過多樣的品質控制；就像汽車或電視機生產的品質控制系統一樣。如果生產的蛋白質出現錯誤，或者生產不平衡，會阻塞生產線，引起各種疾病，包括II型糖尿病、囊性纖維化，以至某些癌症。因此，內質網生產蛋白質的能力至為重要，必須仔細規範和調整，以迎合需求。今年的邵逸夫生命科學與 醫學獎得獎者是森 和俊及彼德．瓦爾特，他們發現了細胞調節內質網裡生產蛋白質的信號通道—即所謂未折疊蛋白反應。
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.
