RESEARCH NEWS & VIEWS Schekman identified many of the genes that control intracellular transport of the cargo-carrying vesicles along the secretory pathway in yeast cells.
Rothman revealed that SNARE proteins mediate membrane fusion that precedes cargo delivery.
Ca2+
On the target membrane, SNARE proteins ‘zip up’ with specific SNAREs on the cargocarrying vesicle, pulling the two membranes together. The membranes subsequently fuse, releasing the cargo.
Secretory pathway Cell surface
Vesicles
Target membrane
SNARE
SNARE
Nucleus Cargo Studying neurons, Sudhof described how the cargo-release machinery communicates with the associated regulatory machinery, which includes calcium.
Vesicle
PHYSIOLOGY OR MEDICINE
Traffic control system within cells The recipients of the Nobel Prize in Physiology or Medicine are Randy W. Schekman, James E. Rothman and Thomas C. Südhof, for their discoveries on how cells deliver thousands of internally generated molecules to the right place at the right time (see figure).
I D E N T I F I C AT I O N O F T H E TRAFFICKING MACHINERY by Susan Ferro-Novick
I
n the late 1970s, Randy Schekman and Jim Rothman both strove to identify the cellular machinery that drives the secretory pathway, albeit by taking strikingly different approaches. Schekman and co-workers took advantage of yeast genetics to initially identify 23 genes, called SEC, whose products are required for protein secretion1,2. Rothman and colleagues used a biochemical approach to purify, by brute force, components of the mammalian secretory apparatus3. As the SEC genes were characterized and several of their mammalian counterparts were identified, it became clear that Schekman and Rothman’s independent approaches had converged and catalysed the field of membrane traffic. Schekman went on to focus on the ‘coat’ proteins that sort cellular cargo into a nascent vesicle. Rothman instead focused on
the membrane-fusion machinery, which he called SNARE proteins4, and which is found in all eukaryotes (organisms that include fungi, plants and animals). The ground-breaking work of these laureates has revolutionized our understanding of a basic cellular function — protein secretion. Whereas the genetic approach identified many of the components of the pathway, the biochemical assays facilitated elucidation of the components’ functions. The laureates’ seminal contributions paved the way for studies of many other cellular processes that rely on the secretory pathway, including cell polarization, cell migration and the degradative process of autophagy.
A TURBOCHARGER FOR MEMBRANE FUSION by Nils Brose
T
he realization that the membrane-fusion machinery is evolutionarily conserved from yeast cells to neurons posed a problem for neuroscientists. SNARE-mediated membrane fusion and protein secretion are rather slow, whereas the secretion of neurotransmitter molecules from synaptic vesicles in neurons occurs with millisecond precision and is tightly controlled by intracellular calcium ions, which can boost the vesicle fusion rate by up to 1 million times. Clearly, neuronal synapses could not rely only on SNAREs. They must contain a specialized protein machinery that boosts the somewhat sluggish SNARE machinery, thereby equipping synapses for their exquisite precision and speed. When Rothman discovered the function of SNAREs in the early 1990s, Tom Südhof was well on his way to a systematic molecular cartography of synaptic communication between neurons and a functional analysis of synaptic-vesicle proteins — an endeavour that was co-pioneered with his long-term ally
9 8 | NAT U R E | VO L 5 0 4 | 5 D E C E M B E R 2 0 1 3
© 2013 Macmillan Publishers Limited. All rights reserved
Reinhard Jahn. Südhof identified and characterized numerous key components of the synaptic-vesicle fusion apparatus and of the parallel regulatory machinery that makes synaptic secretion so fast5. Of greatest importance, he identified synaptotagmin, and showed that this protein is the enigmatic calcium sensor that ‘turbocharges’ synaptic-vesicle secretion6. But the story of this year’s Nobel laureates does not end here. From single-cell organisms to humans, each and every cellular process depends on the cellular logistics of membrane trafficking and the secretion of cellular cargo. Not surprisingly then, diseases as diverse as tetanus, botulism, haemophagocytic lymphohistiocytosis, epilepsy and even schizophrenia have been shown — or are at least thought — to be caused by defects in proteins that control cellular trafficking. And this is just the tip of the iceberg. Interfering with these processes for therapeutic purposes seems only steps away. ■ Susan Ferro-Novick is at the Howard Hughes Medical Institute, Department of Cellular & Molecular Medicine, University of California, San Diego, La Jolla, California 92093-0668, USA. Nils Brose is in the Department of Molecular Neurobiology, Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany. e-mails: [email protected]; [email protected] 1. Novick, P., Field, C. & Schekman, R. Cell 21, 205–215 (1980). 2. Novick, P. & Schekman, R. Proc. Natl Acad. Sci. USA 76, 1858–1862 (1979). 3. Balch, W. E., Dunphy, W. G., Braell, W. A. & Rothman, J. E. Cell 39, 405–416 (1984). 4. Söllner, T. et al. Nature 362, 318–324 (1993). 5. McMahon, H. T., Missler, M., Li, C. & Südhof, T. C. Cell 83, 111–119 (1995). 6. Fernández-Chacón, R. et al. Nature 410, 41–49 (2001).
Rothman revealed that SNARE proteins mediate membrane fusion that precedes cargo delivery.
Ca2+
On the target membrane, SNARE proteins ‘zip up’ with specific SNAREs on the cargocarrying vesicle, pulling the two membranes together. The membranes subsequently fuse, releasing the cargo.
Secretory pathway Cell surface
Vesicles
Target membrane
SNARE
SNARE
Nucleus Cargo Studying neurons, Sudhof described how the cargo-release machinery communicates with the associated regulatory machinery, which includes calcium.
Vesicle
PHYSIOLOGY OR MEDICINE
Traffic control system within cells The recipients of the Nobel Prize in Physiology or Medicine are Randy W. Schekman, James E. Rothman and Thomas C. Südhof, for their discoveries on how cells deliver thousands of internally generated molecules to the right place at the right time (see figure).
I D E N T I F I C AT I O N O F T H E TRAFFICKING MACHINERY by Susan Ferro-Novick
I
n the late 1970s, Randy Schekman and Jim Rothman both strove to identify the cellular machinery that drives the secretory pathway, albeit by taking strikingly different approaches. Schekman and co-workers took advantage of yeast genetics to initially identify 23 genes, called SEC, whose products are required for protein secretion1,2. Rothman and colleagues used a biochemical approach to purify, by brute force, components of the mammalian secretory apparatus3. As the SEC genes were characterized and several of their mammalian counterparts were identified, it became clear that Schekman and Rothman’s independent approaches had converged and catalysed the field of membrane traffic. Schekman went on to focus on the ‘coat’ proteins that sort cellular cargo into a nascent vesicle. Rothman instead focused on
the membrane-fusion machinery, which he called SNARE proteins4, and which is found in all eukaryotes (organisms that include fungi, plants and animals). The ground-breaking work of these laureates has revolutionized our understanding of a basic cellular function — protein secretion. Whereas the genetic approach identified many of the components of the pathway, the biochemical assays facilitated elucidation of the components’ functions. The laureates’ seminal contributions paved the way for studies of many other cellular processes that rely on the secretory pathway, including cell polarization, cell migration and the degradative process of autophagy.
A TURBOCHARGER FOR MEMBRANE FUSION by Nils Brose
T
he realization that the membrane-fusion machinery is evolutionarily conserved from yeast cells to neurons posed a problem for neuroscientists. SNARE-mediated membrane fusion and protein secretion are rather slow, whereas the secretion of neurotransmitter molecules from synaptic vesicles in neurons occurs with millisecond precision and is tightly controlled by intracellular calcium ions, which can boost the vesicle fusion rate by up to 1 million times. Clearly, neuronal synapses could not rely only on SNAREs. They must contain a specialized protein machinery that boosts the somewhat sluggish SNARE machinery, thereby equipping synapses for their exquisite precision and speed. When Rothman discovered the function of SNAREs in the early 1990s, Tom Südhof was well on his way to a systematic molecular cartography of synaptic communication between neurons and a functional analysis of synaptic-vesicle proteins — an endeavour that was co-pioneered with his long-term ally
9 8 | NAT U R E | VO L 5 0 4 | 5 D E C E M B E R 2 0 1 3
© 2013 Macmillan Publishers Limited. All rights reserved
Reinhard Jahn. Südhof identified and characterized numerous key components of the synaptic-vesicle fusion apparatus and of the parallel regulatory machinery that makes synaptic secretion so fast5. Of greatest importance, he identified synaptotagmin, and showed that this protein is the enigmatic calcium sensor that ‘turbocharges’ synaptic-vesicle secretion6. But the story of this year’s Nobel laureates does not end here. From single-cell organisms to humans, each and every cellular process depends on the cellular logistics of membrane trafficking and the secretion of cellular cargo. Not surprisingly then, diseases as diverse as tetanus, botulism, haemophagocytic lymphohistiocytosis, epilepsy and even schizophrenia have been shown — or are at least thought — to be caused by defects in proteins that control cellular trafficking. And this is just the tip of the iceberg. Interfering with these processes for therapeutic purposes seems only steps away. ■ Susan Ferro-Novick is at the Howard Hughes Medical Institute, Department of Cellular & Molecular Medicine, University of California, San Diego, La Jolla, California 92093-0668, USA. Nils Brose is in the Department of Molecular Neurobiology, Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany. e-mails: [email protected]; [email protected] 1. Novick, P., Field, C. & Schekman, R. Cell 21, 205–215 (1980). 2. Novick, P. & Schekman, R. Proc. Natl Acad. Sci. USA 76, 1858–1862 (1979). 3. Balch, W. E., Dunphy, W. G., Braell, W. A. & Rothman, J. E. Cell 39, 405–416 (1984). 4. Söllner, T. et al. Nature 362, 318–324 (1993). 5. McMahon, H. T., Missler, M., Li, C. & Südhof, T. C. Cell 83, 111–119 (1995). 6. Fernández-Chacón, R. et al. Nature 410, 41–49 (2001).
