Autophagy

Autophagy

The Otomo Group

Autophagy is a major catabolic process that protects cells from various dangers. Under starvation, cells promote autophagy to degrade cytoplasmic materials in a non-selective manner. This leads to the internal production of nutrition which allows cells to survive. Cells also use autophagy to selectively remove cytotoxic materials, such as protein aggregates, damaged organelles, and invasive bacteria. These functions of autophagy are crucial in preventing diseases, including cancer, neurodegeneration, and infection. There is growing interest in controlling autophagic activity to treat these diseases. It is critical for that purpose to have a precise understanding of the mechanism of this unique process. An autophagic process begins with forming a double-membrane bound compartment called an autophagosome in the cytoplasm, which results in the encapsulation of cytoplasmic materials within the autophagosome. Upon the fusion with a lysosome, the autophagosome contents are broken down by lysosomal hydrolases to their building blocks, such as amino acids. The crucial part of autophagy is the de novo construction of the autophagosomal membrane. Autophagy related (ATG) proteins work together to prepare the seed membrane and grow it into a balloon-like shape to engulf cytoplasmic materials. Canonical membrane remodeling proteins mediate the completion of autophagosome formation and the subsequent fusion with a lysosome. The Otomo laboratory uses structural and biochemical methods to uncover the molecular mechanisms of autophagy, with a focus on the core ATG proteins essential for autophagosome formation. The Otomo lab elucidated the structure of the ATG12-ATG5-ATG16 complex that stimulates the conjugation of ATGB ubiquitin-like protein to the autophagosomal membrane and uncovered the roles of ATG2 and ATG9 as lipid transporting proteins. Understanding the functions and mechanisms of these ATG proteins led to the first rational model of autophagosome formation. It also opened the door to the rational development of autophagy inhibitors and activators. The laboratory plans to continue its work on these proteins and extend the study toward a more extensive system involving other ATG factors to yield a comprehensive understanding of the mechanisms of autophagy.

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Select Publications

Structure, lipid scrambling activity and role in autophagosome formation of ATG9A. Maeda, S., Yamamoto, H., Kinch, L.N., Garza, C.M., Takahashi, S., Otomo, C., Grishin, N.V., Forli, S., Mizushima, N., Otomo, T.# Nat. Struct. Mol. Biol., 2020, 27, 1194-1201.

The autophagic membrane tether ATG2A transfers lipids between membranes. Maeda, S., Otomo, C., Otomo, T.# eLife, 2019, 8. pii: e45777.

Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A-WIPI4 complex. Chowdhury, S.*, Otomo, C.*, Leitner, A., Ohashi, K., Aebersold, R., Lander, G.C.#, Otomo, T.# Proc. Natl. Acad. Sci. USA. 2018, 115, E9792-E9801

Structural basis of ATG3 recognition by the autophagic ubiquitin-like protein ATG12. Metlagel, Z., Otomo, C., Takaesu, G., Otomo, T.# Proc. Natl. Acad. Sci. USA. 2013, 110, 18844-9.

Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy. Otomo, C., Metlagel, Z., Takaesu, G., Otomo, T.# Nat. Struct. Mol. Biol. 2013, 20, 59-66.

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Our research programs are funded primarily by grants from the National Institutes of Health (NIH). Private donations help to accelerate the progress of research through the purchase of laboratory supplies and equipment or the recruitment of additional laboratory personnel. Thank you!

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