Paper ID: 281
Tokyo Institute of Technology (Japan)
Every cellular component is maintained by balance between synthesis and degradation. Cellular degradation process is highly regulated and plays critical roles in cell physiology. There exist two major pathways of intracellular degradation, lysosome/vacuole- and ubiquitin/proteasome- systems. The former is mediated mainly via autophagy, facilitates principally bulk non-selective degradation. Since discovery of lysosome and coining autophagy as self-eating process by C. de Duve, for long time not much progress had been made about its molecular mechanism.
More than 28 years ago I first found by light microscopy that the yeast, S. cerevisiae, induces massive protein degradation within the vacuole under nutrient starvation. Electron microscopy revealed that membrane dynamics during the process is topologically the same as known macroautophagy in mammals. Taking advantage of the yeast system, we succeeded in isolation of many autophagy-defective mutants. Now we know that 18 ATG genes are essential for starvation-induced autophagy. These Atg proteins function concertedly in the sequestration of cytoplasmic constituents into a specialized membrane structure, the autophagosome. The Atg proteins consist of six functional units, including an Atg1 kinase complex, the PI3 kinase complex and two unique ubiquitin-like conjugation systems. Soon we found that these core ATG genes are well conserved from yeast to mammals. The identification of ATG genes completely changed the landscape of autophagy researches. By genetic manipulation of ATG genes in various organisms and specific organ or individuals, revealed so broad range of physiological functions of autophagy. Not only nutrient recycling, autophagy plays critical roles for intracellular clearance by elimination of harmful proteins, damaged organelles, and bacteria escaped in the cytoplasm. It is getting clear that autophagy is relevant to many diseases such as neurodegeneration, infection and cancer. Now autophagy has become so popular field in cell biology.
We are attempting to elucidate the mechanisms of the unique membrane dynamics during autophagy by studying the structure and function of Atg proteins. Even in yeast autophagy there are many fundamental questions remain to be answered. Further comprehensive and biochemical analyses are required from various points of view. Present our knowledge on the molecular mechanism and physiological roles of autophagy in yeast will be presented and discussed.