News Releases & Research Results Identification of a nuclear proteolytic mechanism induced by liquid–liquid phase separation: A novel proteolytic mechanism that helps cells to adapt to environmental stress

The results of collaborative research led by Research Fellow Sayaka Yasuda, Research Fellow Hikaru Tsuchiya, Executive Director Keiji Tanaka, and Deputy Associate Director Research Fellow Yasushi Saeki of the Laboratory of Protein Metabolism at Tokyo Metropolitan Institute of Medical Science; Dr. Rubén Fernández-Busnadiego (Group Leader) and Professor Wolfgang Baumeister of the Max Planck Institute of Biochemistry; Professor Toshifumi Inada of Tohoku University; and Professor Shigeo Murata of the University of Tokyo.

• A novel mechanism of proteolysis that cells utilize to adapt to environmental stress were identified.
• The ubiquitin-proteasome system (*1) is involved in the degradation of proteins in cells. The authors demonstrated that the interaction of ubiquitin-binding proteins and ubiquitin chains induces liquid-liquid separation (*2), and that the recruitment of proteasome (*3) to the system leads to the formation of a nuclear proteasome droplet.
  *1: The ubiquitin-proteasome system is one of the main protein degradation systems that is similar to the autophagy/lysosome system. It controls various cellular functions such as cell proliferation, signaling, and protein quality control.
  *2: Liquid-liquid separation is a phenomenon in which two immiscible liquids are separated into two phases.
  *3: Proteasome is a large, ATP-dependent proteolytic enzyme complex that selectively recognizes and degrades proteins that are labeled by a ubiquitin chain.
• Detailed analysis revealed that the nuclear proteasome droplet functions as a proteolytic compartment for proteins that are abnormally expressed in the nucleus.
• The findings provide insights into the mechanism of abnormal proteolysis, which is associated with tumor formation and neurodegenerative diseases.

This research project was conducted with the support of Advanced Research & Development Programs for Medical Innovation, unit-type (AMED-CREST) by AMED.

The results of research were published in Nature, a British scientific journal on February 6.

Yasuda S., et al. Stress- and ubiquitylation-dependent phase separation of the proteasome Nature
DOI：10.1038/s41586-020-1982-9