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Related Grants-in-Aid for Scientific Research:��FY2003-2007 Grant-in-Aid for Scientific Research on Priority Areas: “Cellular mechanism and functions of transport network based on lysosomes”�FY2008-2012 Grant-in-Aid for Scientific Research on Innovative Areas: “Role of intracellular decomposition logistics in disease and analysis of its driving mechanism”�

2.Introduction of KAKENHI Projects

【Background】�Cells transport proteins and other substan-ces to their intracellular digestive organs known as lysosomes to be decomposed and recycled into new proteins or energy resources. A mechanism to bring extracel-lular substances into the cell and carry them to lysosomes is called endocytosis, while a mechanism to carry intracellular substances to lysosomes is called autopha-gy (Fig. 1). Autophagy works when a cell decomposes intracellular substances to use them as nutrients in case of starva-tion. Autophagy has begun to attract much attention from researchers as it was recently found that it cleans unfavorable substances inside the cell to help prevent the development of infectious diseases, Alzheimer's and other disorders. The two mechanisms for transporting substances to lysosomes had been believed to be elab-

orately controlled just like logistic sys-tems in our society. But whether this was the case remained unclear until recently.��【Results】�Our research team found two factors that are combined with Beclin, a factor in-volved in autophagy. We named the two factors Atg14L and Rubicon. When Atg14L is combined with Beclin, autopha-gy is promoted. Beclin combined with Ru-bicon inhibits both autophagy and endocy-tosis (Fig. 3). In other words, the two factors act as a switch through Beclin. Ru-bicon controls autophagy and endocytosis simultaneously.��【Outlook】�It is widely known that mice with de-stroyed Beclin genes develop cancer spon-taneously. We believe that cells can prob-

ably be prevented from becoming cancerous when the functions of the two factors discovered by our team work prop-erly. We may be able to find a clue to can-cer prevention in our future research. Au-tophagy has become the hottest issue in life science as it was learned recently that autophagy is also involved in a wide range of medical issues such as inflamma-tory reaction, heart failure, diabetes inhibi-tion, life extension and immune control. Japan leads the world in autophagy re-search. Our group wants to further our re-search on intracellular logistics, which is transport control of substances for intra-cellular recycling. We hope to help Japan, as the leading nation, to generate and dis-tribute lots of research results, which will also be useful for medical applications.

Fig. 1 �In cells, various pathways to transport intracellular substances form a network similar to a transport system network in the human society.

Fig. 3�Beclin shows a different control function, depending on which factor is combined with it.

Fig. 2�Upper: In autophagy, an organelle called autophagosome swal-lows up protein and others to transport them to a lysosome to de-compose for recycling. �Lower: An electron microscopic photo of an autophagosome swal-lowing up a microbe. We have discovered that in autophagy, mi-crobes that invade the cell are also caught and decomposed, like intracellular substances.

BiologicalDiscovery of integrated mechanism to control intracellular recycling system of substances

Tamotsu Yoshimori�Professor�

Osaka University