Monday, October 24, 2016
Sunday, October 23, 2016
Nobel Laureate in Physiology and Medicine, 2016
Citation from: https://www.nobelprize.org/nobel_prizes/medicine/laureates/2016/press.html
Yoshinori Ohsumi
Yoshinori Ohsumi was
born 1945 in Fukuoka, Japan. He received a Ph. D. from University of Tokyo in
1974. After spending three years at Rockefeller University, New York, USA, he
returned to the University of Tokyo where he established his research group in
1988. He is since 2009 a professor at the Tokyo Institute of Technology.
Prize motivation: "for his discoveries of mechanisms for autophagy"
Prize share: 1/1
Summary
This
year's Nobel Laureate discovered and elucidated mechanisms underlying autophagy,
a fundamental process for degrading and recycling cellular components.
The
word autophagy originates from the Greek words auto-,
meaning "self", and phagein, meaning "to eat". Thus,
autophagy denotes "self-eating". This concept emerged during the
1960's, when researchers first observed that the cell could destroy its own
contents by enclosing it in membranes, forming sack-like vesicles that were transported
to a recycling compartment, called the lysosome, for
degradation. Difficulties in studying the phenomenon meant that little was
known until, in a series of brilliant experiments in the early 1990's,
Yoshinori Ohsumi used baker's yeast to identify genes essential for autophagy.
He then went on to elucidate the underlying mechanisms for autophagy in yeast
and showed that similar sophisticated machinery is used in our cells.
Ohsumi's
discoveries led to a new paradigm in our understanding of how the cell recycles
its content. His discoveries opened the path to understanding the fundamental
importance of autophagy in many physiological processes, such as in the
adaptation to starvation or response to infection. Mutations in autophagy genes
can cause disease, and the autophagic process is involved in several conditions
including cancer and neurological disease.
Degradation – a central function in all living cells
In
the mid 1950's scientists observed a new specialized cellular compartment,
called an organelle, containing enzymes that digest proteins,
carbohydrates and lipids. This specialized compartment is referred to as a
"lysosome" and functions as a workstation for degradation of
cellular constituents. The Belgian scientist Christian de Duve was awarded the
Nobel Prize in Physiology or Medicine in 1974 for the discovery of the
lysosome. New observations during the 1960's showed that large amounts of
cellular content, and even whole organelles, could sometimes be found inside
lysosomes. The cell therefore appeared to have a strategy for delivering large
cargo to the lysosome. Further biochemical and microscopic analysis revealed a
new type of vesicle transporting cellular cargo to the lysosome for degradation
(Figure 1). Christian de Duve, the scientist behind the discovery of the
lysosome, coined the term autophagy, "self-eating", to describe this
process. The new vesicles were named autophagosomes.
Figure 1: Our cells
have different specialized compartments.
Lysosomes
constitute one such compartment and contain enzymes for digestion of cellular
contents. A new type of vesicle called autophagosome was observed within the
cell. As the autophagosome forms, it engulfs cellular contents, such as damaged
proteins and organelles. Finally, it fuses with the lysosome, where the
contents are degraded into smaller constituents. This process provides the cell
with nutrients and building blocks for renewal.
During
the 1970's and 1980's researchers focused on elucidating another system used to
degrade proteins, namely the "proteasome". Within this research field
Aaron Ciechanover, Avram Hershko and Irwin Rose were awarded the 2004 Nobel
Prize in Chemistry for "the discovery of ubiquitin-mediated protein
degradation". The proteasome efficiently degrades proteins one-by-one, but
this mechanism did not explain how the cell got rid of larger protein complexes
and worn-out organelles. Could the process of autophagy be the answer and, if
so, what were the mechanisms?
A groundbreaking experiment
Yoshinori
Ohsumi had been active in various research areas, but upon starting his own lab
in 1988, he focused his efforts on protein degradation in the vacuole,
an organelle that corresponds to the lysosome in human cells. Yeast cells are
relatively easy to study and consequently they are often used as a model for
human cells. They are particularly useful for the identification of genes that
are important in complex cellular pathways. But Ohsumi faced a major challenge;
yeast cells are small and their inner structures are not easily distinguished
under the microscope and thus he was uncertain whether autophagy even existed
in this organism. Ohsumi reasoned that if he could disrupt the degradation
process in the vacuole while the process of autophagy was active, then
autophagosomes should accumulate within the vacuole and become visible under
the microscope. He therefore cultured mutated yeast lacking vacuolar
degradation enzymes and simultaneously stimulated autophagy by starving the
cells. The results were striking! Within hours, the vacuoles were filled with
small vesicles that had not been degraded (Figure 2). The vesicles were
autophagosomes and Ohsumi's experiment proved that authophagy exists in yeast
cells. But even more importantly, he now had a method to identify and characterize
key genes involved this process. This was a major break-through and Ohsumi
published the results in 1992.
Figure 2: In yeast
(left panel) a large compartment called the vacuole corresponds
to the lysosome in mammalian cells.
Ohsumi
generated yeast lacking vacuolar degradation enzymes. When these yeast cells
were starved, autophagosomes rapidly accumulated in the vacuole (middle panel).
His experiment demonstrated that autophagy exists in yeast. As a next step,
Ohsumi studied thousands of yeast mutants (right panel) and identified 15 genes
that are essential for autophagy.
Autophagy genes are discovered
Ohsumi
now took advantage of his engineered yeast strains in which autophagosomes
accumulated during starvation. This accumulation should not occur if genes
important for autophagy were inactivated. Ohsumi exposed the yeast cells to a
chemical that randomly introduced mutations in many genes, and then he induced
autophagy. His strategy worked! Within a year of his discovery of autophagy in
yeast, Ohsumi had identified the first genes essential for autophagy. In his
subsequent series of elegant studies, the proteins encoded by these genes were
functionally characterized. The results showed that autophagy is controlled by
a cascade of proteins and protein complexes, each regulating a distinct stage
of autophagosome initiation and formation (Figure 3).
Figure 3: Ohsumi
studied the function of the proteins encoded by key autophagy genes.
He
delineated how stress signals initiate autophagy and the mechanism by which
proteins and protein complexes promote distinct stages of autophagosome
formation.
Autophagy – an essential mechanism in our cells
After
the identification of the machinery for autophagy in yeast, a key question
remained. Was there a corresponding mechanism to control this process in other
organisms? Soon it became clear that virtually identical mechanisms operate in
our own cells. The research tools required to investigate the importance of
autophagy in humans were now available.
Thanks
to Ohsumi and others following in his footsteps, we now know that autophagy
controls important physiological functions where cellular components need to be
degraded and recycled. Autophagy can rapidly provide fuel for energy and
building blocks for renewal of cellular components, and is therefore essential
for the cellular response to starvation and other types of stress. After
infection, autophagy can eliminate invading intracellular bacteria and viruses.
Autophagy contributes to embryo development and cell differentiation. Cells
also use autophagy to eliminate damaged proteins and organelles, a quality
control mechanism that is critical for counteracting the negative consequences
of aging.
Disrupted
autophagy has been linked to Parkinson's disease, type 2 diabetes and other
disorders that appear in the elderly. Mutations in autophagy genes can cause
genetic disease. Disturbances in the autophagic machinery have also been linked
to cancer. Intense research is now ongoing to develop drugs that can target
autophagy in various diseases.
Autophagy
has been known for over 50 years but its fundamental importance in physiology
and medicine was only recognized after Yoshinori Ohsumi's paradigm-shifting
research in the 1990's. For his discoveries, he is awarded this year's Nobel
Prize in physiology or medicine.
Key publications
Takeshige,
K., Baba, M., Tsuboi, S., Noda, T. and Ohsumi, Y. (1992). Autophagy in yeast
demonstrated with proteinase-deficient mutants and conditions for its
induction. Journal of Cell Biology 119, 301-311
Tsukada,
M. and Ohsumi, Y. (1993). Isolation and characterization of autophagy-defective
mutants of Saccharomyces cervisiae. FEBS Letters 333, 169-174
Mizushima,
N., Noda, T., Yoshimori, T., Tanaka, Y., Ishii, T., George, M.D., Klionsky,
D.J., Ohsumi, M. and Ohsumi, Y. (1998). A protein conjugation system essential
for autophagy. Nature 395, 395-398
Ichimura,
Y., Kirisako T., Takao, T., Satomi, Y., Shimonishi, Y., Ishihara, N., Mizushima,
N., Tanida, I., Kominami, E., Ohsumi, M., Noda, T. and Ohsumi, Y. (2000). A
ubiquitin-like system mediates protein lipidation. Nature, 408, 488-492
Labels:
Autophagy