Shin-biology regulated by protein lifetime

Grant-in-Aid for Transformative Research Areas (A) FY2023–FY2027, MEXT Japan

Planned Research

Regulation of lifespan of organelle component proteins
Koji Yamano
Medical Research Institute, Tokyo Medical and Dental University
Yuko Fujioka
Biological Molecular Mechanisms, Institute for Genetic Medicine, Hokkaido University

The branched ubiquitin chains are considered as one of the key ubiquitin code regulating protein lifespan. We have found that the branched ubiquitin chains are abundant ubiquitin modifications in cells and promote protein degradation through the proteasome. Therefore, this research project aim at elucidating the role of the ubiquitin chain branching enzymes and branched ubiquitin codes in the regulation of protein lifespan.

  1. Regulation of protein lifespan by the ubiquitin chain branching enzymes
    Identification of target proteins regulated by the ubiquitin chain branching enzymes
  2. Lifespan of the E3 ubiquitin ligases
    Elucidating the mechanism of the code conversion from K63-linked chains to the branched ubiquitin chains
  3. Signaling pathways modifying protein lifespan
    Elucidating the mechanism how signal transduction pathways regulate the protein lifespan.
  1. Hayashida R, Kikuchi R, Imai K, Kojima W, Yamada T, Iijima M, Sesaki H, Tanaka K, *Matsuda N, *Yamano K. Elucidation of ubiquitin-conjugating enzymes that interact with RBR-type ubiquitin ligases using a liquid-liquid phase separation-based method. J Biol Chem 299, 102822 (2023)
  2. Kojima W, *Yamano K, Kosako H, Imai K, Kikuchi R, Tanaka K, Matsuda N. Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy. Autophagy 17, 2011-2036 (2021)
  3. *Yamano K, Kikuchi R, Kojima W, Hayashida R, Koyano F, Kawawaki J, Shoda T, Demizu Y, Naito M, Tanaka K, *Matsuda N. Critical role of mitochondrial ubiquitination and the OPTN-ATG9A axis in mitophagy. J Cell Biol 219, e201912144 (2020)
  4. Fujioka Y, Alam JM, Noshiro D, Mouri K, Ando T, Okada Y, May AI, Knorr RL, Suzuki K, Ohsumi Y, *Noda NN. Phase separation organizes the site of autophagosome formation. Nature 578, 301-305 (2020)
  5. *Yamano K, Wang C, Sarraf SA, Münch C, Kikuchi R, Noda NN, Hizukuri Y, Kanemaki MT, Harper W, Tanaka K, *Matsuda N, *Youle RJ. Endosomal Rab cycles regulate Parkin-mediated mitophagy. eLife 7, e31326 (2018)
  6. #Yamamoto H, #Fujioka Y (#co-first), #Suzuki SW, Noshiro D, Suzuki H, Kondo-Kakuta C, Kimura Y, Hirano H, Ando T, *Noda NN, *Ohsumi Y. The intrinsically disordered protein Atg13 mediates supramolecular assembly of autophagy initiation complexes. Dev Cell 38, 86-99 (2016)
  7. Yamano K, Fogel AI, Wang C, van der Bliek AM, *Youle RJ. Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy. eLife 3, e01612 (2014)
  8. Hasson SA, Kane LA, Yamano K, Huang CH, Sliter DA, Buehler E, Wang C, Heman-Ackah SM, Hessa T, Guha R, Martin SE, *Youle RJ. High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Nature 504, 291-295 (2013)
  9. #Ohnishi M, #Yamano K (#co-first), *Sato M, *Matsuda N, *Okamoto K. Molecular mechanisms and physiological functions of mitophagy. EMBO J 40, e104705 (2021)
  10. *Yamano K, Matsuda N, Tanaka K. The ubiquitin signal and autophagy: an orchestrated dance leading to mitochondrial degradation. EMBO Rep 17, 300-316 (2016)