The Nobel Prizein

Medicine2016

Bui Dac Chi,MDMedic Center

Autophagy, a method for breaking down and recycling large pieces of cellular junk, such as clusters of damaged proteins or worn-out organelles

Molecular biologist Yoshinori Ohsumi has won the 2016 Nobel Prize in Physiology or Medicine for his work in the field of autophagy: the processes by which the cell digests and recycles its own components The 71-year-old Ohsumi, who is currently a professor at the Tokyo Institute of Technology in Yokohama, was recognized for his experiments in the 1990s, when he used baker's yeast (Saccharomyces cerevisiae) to identify genes that control how cells destroy their own contents. The same kinds of mechanism operate in human cells — and are sometimes involved in genetic diseas The word 'autophagy' — from the Greek for 'self-eating' — was coined in 1963 by the Belgian biochemist Christian de Duve, who saw how cells broke down their parts inside a waste-processing sac that he called a lysosome. Biologists now understand that this process is fundamentally important to living cells.

Autophagy is a general term for the degradation of cytoplasmic components within lysosomes This process is quite distinct from endocytosis-mediated lysosomal degradation of extracellular and plasma membrane proteins. There are three types of autophagy— macroautophagy, microautophagy, and chaperone-mediated autophagy—and the term “autophagy” usually indicates macroautophagy unless otherwise specified . Autophagy is mediated by a unique organelle called the autophagosome. As autophagosomes engulf a portion of cytoplasm, autophagy is generally thought to be a nonselective degradation system. This feature is in marked contrast to the ubiquitin–proteasome system, which specifically recognizes only ubiquitinated proteins for proteasomal degradation. It is therefore reasonable to assume that the ubiquitin–proteasome system has numerous specific functions because it can selectively degrad thousands of substrates.

• Discovery of the autophagy machinery

• Finding the autophagy machinery let Ohsumi study it in detail. A year later, he discovered as many as 15 genes needed for the machinery to work. In the following years, Ohsumi and other scientists examined the proteins encoded by these genes and began to figure out how the components of the “bulk waste” bag, or autophagosome, came together, and then fused with the lysosome.

• The work revealed something new about the cell’s garbage centers, Zierath said. “Before Ohsumi came on the scene, people understood that the waste dump was in the cell,” she said. “But what he showed was that it wasn’t a waste dump. It was a recycling plant.”

Keeping this recycling machinery in good working condition is crucial for cells’ health. Not enough recycling can cause cellular trash to build up and lead to neurological diseases such as Alzheimer’s and Parkinson’s. Too much recycling, on the other hand, has been linked to cancer .

Recent studies have clearly demonstrated that autophagy has a greater variety of physiological and pathophysiological roles than expected, such as starvation adaptation, intracellular protein and organelle clearance, development, anti-aging, elimination of microorganisms, cell death, tumor suppression, and antigen presentation. Additionally, in some situations, the contribution of autophagy seems to be very complicated. For example, it is very difficult to generalize the role of autophagy in cancer and cell death. This is like the question: “Is inflammation good or bad for life?” Of course, inflammation is required for the anti-bacterial response, but the inflammatory response associated with bacterial pneumonia can be life-threatening. Therefore, it may be difficult to draw simplified connections between autophagy and higher-order functions.

Our knowledge of autophagy now seems to be ready for therapeutic application. Indeed, small molecules that can regulate autophagy seem to have greatpotential to modulate the clinical course of neurodegenerative diseases . In addition, pharmacologic inhibition of autophagy was reported to promote chemotherapeutic response in a mouse model for lymphoma . More connections between autophagy and disease will likely be demonstrated in the very near future.

• Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. Despite its simplicity, recent progress has demonstrated that autophagy plays a wide variety of physiological and pathophysiological roles, which are sometimes complex. Autophagy consists of several sequential steps—sequestration, transport to lysosomes, degradation, and utilization of degradation products—and each step may exert different function.

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