The Shaw Prize in Life Science and Medicine 2021 is awarded to Scott D Emr, Frank HT Rhodes Class of 1956 Professor of Molecular Biology and Genetics and Director of the Weill Institute for Cell and Molecular Biology, Cornell University, USA for the landmark discovery of the ESCRT (Endosomal Sorting Complex Required for Transport) pathway, which is essential in diverse processes involving membrane biology, including cell division, cell-surface receptor regulation, viral dissemination, and nerve axon pruning. These processes are central to life, health, and disease.
For life to be possible, cells must put particular bio-components in the proper location and at the proper time. Here is where this year’s Shaw Laureate in Life Science and Medicine, Scott Emr, comes in. Emr made seminal discoveries in the field of intra-cellular vesicle trafficking. Vesicles are small membrane-bound, fluid-filled sacs that transport bio-components to different destinations inside cells. The destinations are called organelles, which are membrane-bound entities responsible for distinct cellular functions. In a landmark series of studies, Emr used elegant genetic strategies that enabled him to identify 40 genes that encode the components of the so-called ESCRT pathway (ESCRT stands for Endosomal Sorting Complex Required for Transport). Emr combined molecular, biochemical, and structural approaches to characterize the 40 ESCRT proteins and to elucidate their individual and combined roles. His work revealed that ESCRT is a bio-machine that interacts with vesicles harbouring newly synthesized proteins and ensures that the vesicles and their cargos are selectively trafficked to distinct subcellular organelles. Central to this work was Emr’s discovery of an enzyme, a lipid kinase, that converts the lipid molecule called phosphatidylinositol to phosphatidylinositol-3-phosphate. By studying this enzyme and the lipids involved, Emr recognized that different lipids function as specific organelle “addresses” that determine the destination to which particular bio-components are delivered. Conversion of one phosphoinositide into another underlies recognition of the organelle membrane surface by the ESCRT pathway. Thus, these lipid “addresses” dictate the precise, sequential progression of vesicle transport from one organelle destination to the next. Remarkably, it takes five ESCRT sub-complexes for full transport between the various vesicle destinations. Emr systematically defined the components in each of five functionally distinct ESCRT machines and characterized the jobs performed by all five in an assembly line-like pathway. Another groundbreaking discovery concerns Emr’s work showing that the ESCRT pathway recognizes a so-called ubiquitin tag on proteins destined to be packaged into vesicles and subsequently targeted to a specialized cellular compartment for destruction. This is a process that is essential for the normal turnover of receptor proteins in cells. In dogma-overturning work, Emr discovered and elucidated that the ESCRT machinery bends vesicle membranes inward and away from the cell cytoplasm. Inward membrane bending enables formation of unique vesicular structures possessing the opposite topology of other well-known subcellular organelles. ESCRT-directed bending of membranes is now accepted as a universal mechanism widely used by cells. Indeed, membrane bending is crucial for many vital processes including the regulation of signaling by cell surface receptors, the separation of daughter cells during cell division, the budding of viruses like HIV from a host cell, allowing the spread of infection to new cells, and for the pruning of neuronal axons, a requirement for normal brain development. Mutations in the ESCRT pathway have been shown to produce profound defects in development, resulting in embryonic lethality, in some cases due to inability to turn off signaling from cell surface receptors such as Notch. In summary, Scott Emr has transformed our understanding of the pathways and mechanisms involved in membrane trafficking, a process that is central to life, from yeast to humans.
Life Science and Medicine Selection Committee
The Shaw Prize
1 June 2021 Hong Kong