Research

Investigation of Molecular Machinery of the Organelles Network to Understand Its Pathophysiology

The Project Leader's Profile

Tamotsu Yoshimori

Department of Cellular Regulation, Research Institute for Microbial Diseases, Professor

Project Leader
  • Tamotsu Yoshimori, Professor
Research Members
  • Takeshi Noda , Associate Professor
  • Eiji Morita, GCOE Research Associate
  • Kouichi Matsunaga, Postdoctoral research fellow
  • Naonobu Fujita, Postdoctoral research fellow
  • Kanae Shirahama-Noda, Postdoctoral research fellow
  • Christopher K. E. Bleck, Technician

Summary

Investigation of Molecular Machinery of the Organelles Network to Understand Its Pathophysiology
Most membrane-bound organelles inside eukaryotic cells are linked to each other by dynamic membrane trafficking. This organelles network is essential not only for the survival of all cells but also for the functions of multicellular networks such as the nervous and immune systems. We aim to elucidate the molecular mechanisms behind membrane trafficking and the roles they play in normal and diseased animal physiology. This knowledge will in turn help improve clinical medical understanding and practice. We are currently focusing on two trafficking routes, namely, autophagy and the endocytic pathway.

Autophagy is a membrane trafficking process that delivers cytoplasmic components to lysosomes for bulk degradation. The process is mediated by the formation of the double membrane-bound autophagosomes. By identifying proteins involved in autophagy in mammalian cells, we have helped to elucidate its molecular basis. In addition, identification of the autophagy-related proteins enabled us to discover a novel physiological role of autophagy, as we found that Group A Streptococcus invading host cells are engulfed by a large autophagosome in the cytosol and then eventually killed. This finding indicates that not only does autophagy play its well known role in metabolism, it also functions in innate immunity. Furthermore, we found that autophagy participates in removing misfolded proteins that could otherwise gradually accumulate, aggregate and damage the cell. Thus, autophagy may protect against diseases such as Alzheimer's and Creutzfeldt-Jakob disease, which result from the accumulation of misfolded proteins. We are currently analyzing in more detail the molecular mechanisms behind autophagosome formation and its intracellular dynamics along with examining the cell-protective role of autophagy .

Endosomes receive macromolecules taken up by endocytosis from the outside. The cargo is then either sorted to lysosomes or recycled back to the plasma membrane. It is important to maintain a balance between the volume of these two flows because an imbalance can, for example, cause cells to turn cancerous. We are currently investigating the mechanism of this sorting process. 

15yoshimori_eng.jpg Figure.
Lower: schema of the autophagic process. Upper left: we have revealed that the Atg16L complex recruits LC3 to autophagosome. We also found LC3 is involved in closure of autophagosome. Upper middle and right: we discovered a new role of autophagy; elimination of pathogenic group A Streptococcus invading cells.

Some of Recent Papers

  1. Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, Maejima I, Shirahama-Nod, K, Ichimura I, Isobe T, Akira S, Noda N, and Yoshimori T. Two Beclin-1 binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nature Cell Biol., DOI: 10.1038/ncb1846, 2009. 
  2. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O, Yoshimori T, and Akira S. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature, 456, 264-268, 2008.
  3. Fujita N, Hayashi M, Fukumoto H, Omori H, Yamamoto A, Noda T, and Yoshimori T. An Atg4B Mutant Hampers the Lipidation of LC3 Paralogues and Causes Defects in Autophagosome Closure. Mol. Biol. Cell, 19, 4651-4659, 2008.
  4. Fujita N, Itoh T, Fukuda M, Noda T, Yoshimori T. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol. Biol. Cell, 19, 2092-2100, 2008.
  5. Nakagawa, I., Amano, A., Mizushima, N., Yamamoto, A., Yamaguchi, H., Kamimoto, T., Nara, A., Funao, J., Nakata, M., Tsuda, K., Hamada, S. and Yoshimori, T. Autophagy defenses cells against invading group A Streptococcus. Science 306, 1037-1040, 2004.