https://www.sciencedaily.com/releases/2016/10/161003103237.htm
The Nobel Assembly at Karolinska Institutet
has today decided to award the 2016 Nobel Prize in Physiology or Medicine to
Yoshinori Ohsumi for his discoveries of mechanisms for autophagy.
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. 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.
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. 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.
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.
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
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.
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