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autophagy

Autophagy has been known for over 50 years bus 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.

For pioneering the molecular elucidation of autophagy, an essential intracelular, degradation system and when disordered, is linked to many diseases including neurodegeneration, cancer, and infection.

Dr. Yoshinori Ohsumi was born in Fukuoka in 1945. In 1963, he entered to The Univ. of Tokyo, and then he chose decisively to follow molecular biology as the path of his future. As a graduate student, Dr. Oshumi studied the initiation mechanism of E. coli ribosome and then action of colicin E3, which inhibits the translation of E.coli cells by binding to its receptor. Near the end of 1974, he enrolled in Rockefeller Univ., to study under Dr. G. M. Edelman. First Dr. Oshumi worked on in vitro fertilization in mice, then switched to work on the mechanism of initiation of DNA replication using yeast, which introduced him to yeast research. Dr. Ohsumi returned to Japan at the end of 1977, and worked as an assistant professor under Prof. Y. Anraku, at the Faculty of Science. The Univ. of Tokyo. Dr Ohsumi decided to take up the study of the yeast vacuolar membrane.

Dr. T. Yoshinori and N. Mizushima in his lab started studies on ATG genes in mammals and a student also worked on plant, proving studies on ATG system is well conserved in higher eukaryotes. However up to now, Dr. Ohsumi has focused on dissection of the molecular mechanism of the ATG proteins in yeast.

Autophagy is a process by which cellular components are captured into organelles called autophagosomes and then brought to the lysosome or vacuole to be broken down and recycled for other uses. It frequently comes into play during starvation, allowing cells to survive periods of privation.

He has:

  • Identified most of the proteins and pathways involved in the process
  • Demonstrated how they are regulated by proteins that sense cells metabolic states
  • Started to outline the fine mechanistic details of autophagosome formation in yeast

“The vacuole was thought to be just a garbage can in the cell, and nor very may people were interested in its physiology, so I thought it would be good to study transport in the vacuole because I would not have much competition. Another reason I chose study vacuole physiology is that, while I was in Dr. Edelman’s lab. We had tried to isolate nuclei from yeast cells, and along the way we discovered that it was easy to get pure preparations of vacuoles. Using these preparations, I was able to find many active transport systems in the vacuolar membrane, including the vacuolar-type ATPase that pumps protons into the vacuole”. (1992, The Rockefeller University Press).

I had a very simple idea: the vacuole can be detected under the light microscope, and it was already considered to be a garbage compartment where protein degradation takes place. So, I thought it would be easy to observe morphological change in the vacuoles of cells that were undergoing lots of degradation. Cell differentiation processes require lots of protein degradation, so I looked at vacuolar proteinase-deficient mutants, which cannot sporulate as normal cells do under nitrogen-starvation conditions, to see if I could observe any changes to vacuolar structure”.

The Nobel Assembly at Karolinska Institute has decided to award the 2016 Nobel Prize in Physiology or Medicine to Yoshinori Oshumi for his discoveries of mechanisms for autophagy (2016-10-03):

This year´s Nobel Laureate discovered and elucidated mechanisms underlying autophagy, a fundamental process for degrading and recycling cellular components.

Summary

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 researches 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.  Brilliant experiments in the early 1990´s, Yoshinori Ohsumi used baker´s yeast to identify genes essential for autophagy in yeast and showed that similar sophisticated machinery is used in our cells. 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 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. 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 are named autophagosomes.

During the 1970´s and 1980´s researchers focused on elucidating another system used to degrade proteins, namely the “proteasome”. Aaron Ciechanover, Avram Hershko and Irwin Rose were awarded the 2004 Nobel Prize in Chemistry for “the discovery of ubiquitin-mediated protein degradation”.

A groundbreaking experiment

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.

Autophagy genes are discovered

Ohsumi exposed the yeast cells to a chemical that randomly introduced mutations in many genes, and then he induced autophagy. His strategy worked, identified the first genes essential for autophagy. 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. He studied thousands of yeast mutants and identified 15 genes that are essential for autophagy and 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

Thanks to Ohsumi, 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, autophgy 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

Mutations in autophagy genes can cause genetic disease. Disturbances in the autophagic machinery have also been linked to cancer. Research is now ongoing to develop drugs that can target autophagy in various diseases.

Biography Yoshinori Ohsumi

  • 2016-present  Professor, Institute of Innovative Research, Tokyo Institute of Technology
  • 2014-present  Honorary Professor, Tokyo Institute of Technology
  • 2010-2016    Professor, Frontier Research Center, Tokyo Institute of Technology
  • 2009-2010    Professor, Advanced Research Organization, Integrated Research Institute, Tokyo Institute of Technology
  • 2004-2009    Professor, The Graduate University for Advanced Studies [SOKENDAI]
  • 1996-2009    Professor, Department of Cell Biology, National Institute for Basic Biology
  • 1988-1996    Associate Professor, Department of Biology, College of Arts and Sciences, The University of Tokyo
  • 1986-1988    Lecturer, Department of Biology, Faculty of Science, The University of Tokyo
  • 1977-1986    Research Associate, Department of Biology, Faculty of Science, The University of Tokyo, with Prof. Yasuhiro Anraku
  • 1974-1977    Postdoctoral Fellow, Rockefeller University with Prof. Gerald M. Edelman
  • 1972-1974    Research Fellow, Department of Agricultural Chemistry, Faculty of Agriculture, The University of Tokyo
  • 1967-1972    Graduate Student, Department of Biochemistry, College of Arts and Sciences, The University of Tokyo, with Prof. Kazutomo Imahori
  • 1963-1967    Undergraduate Student, Department of Basic Science, College of Arts and Sciences, The University of Tokyo Awards

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

Related Links

  • Yoshinori Ohsumi wins medicine Nobel Prize

https://www.youtube.com/watch?v=81W5OwTdxjw

  • Autophagy

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