Clarification of novel glycan catabolic pathways by free glycan analysis of budding yeast and its application to human rare genetic disorders

2022 Fiscal Year Final Research Report

• Project/Area Number: 18H03990
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Tadashi Suzuki 国立研究開発法人理化学研究所, 開拓研究本部, 主任研究員 (90345265)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Keywords: オリゴ糖転移酵素 / 遊離糖鎖 / ユビキチンリガーゼ / 初代肝細胞 / フォールディング

Outline of Final Research Achievements

In S. cerevisiae, hydrolysis activity of OST was enhanced in hrd1 mutant, a ubiquitin ligase involved in endoplasmic reticulum-associated degradation (ERAD). After detailed analyses, it was found that formation of OST-mediated free glycans are enhanced under conditions of enhanced accumulation of unfolded proteins, such as ER stress conditions, and free glycans are suggested to play a role on promoting protein folding and/or preventing misfolded proteins from forming protein aggregates. On the other hand, in mammalian cells we established a method for analyzing serum free glycans, for which OST is believed to be involved in the formation, and identified several novel structures. Furthermore, using rat primary hepatocytes it was shown that liver is indeed involved in the secretion of OST-derived serum free glycans.

Free Research Field

糖鎖代謝生化学

Academic Significance and Societal Importance of the Research Achievements

我々が新たに見出したオリゴ糖転移酵素の加水分解反応は、ドナー基質を加水分解する、という一見無駄な反応であるが、出芽酵母ではタンパク質のフォールディング促進やタンパク質凝集の抑制に関わる可能性が示された。一方哺乳動物細胞では、その加水分解反応が出芽酵母に比べて格段に促進されているが、肝臓が血清に遊離糖鎖を放出できるように進化的に獲得した機能であることが推察される。血清遊離糖鎖の機能はまだ不明であるが、さまざまな免疫反応の調整に関わる可能性が考えられる。