Physiological and pathological roles of GPI side chains and free GPI

2020 Fiscal Year Final Research Report

• Project/Area Number: 16H04753
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Structural biochemistry
• Research Institution: Osaka University
• Principal Investigator: Kinoshita Taroh 大阪大学, 微生物病研究所, 寄附研究部門教授 (10153165)
• Project Period (FY): 2016-04-01 – 2021-03-31
• Keywords: 糖脂質

Outline of Final Research Achievements

Glycosylphosphatidylinositols (GPIs) are glycolipids that are attached to various proteins and act as their membrane anchors on the cell surface. GPIs also exist as free, non-protein linked glycolipids. The structure of core glycan part is conserved whereas side chains make variation. We aimed to clarify how GPI side chains are synthesized and to understand intracellular dynamics and pathological roles of free GPIs. We identified two enzymes that are involved in generation of a major side chain in mammalian GPI. Concerning free GPI, we found that GPIs synthesized in the endoplasmic reticulum of cells defective in GPI transamidase that transfers GPI to proteins, are transported to the cell surface. Using free GPI levels as a measure of GPI biosynthesis levels, we found a mechanism of GPI biosynthesis regulation. We also demonstrated that abnormally accumulated free GPIs cause autoinflammation.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

ヒトが持つタンパク質の約160種には糖脂質であるGPI（グリコシルホスファチジルイノシトール）が結合しており、GPIによって細胞膜に係留されて機能している。GPIの生合成が異常になると先天性グリコシルホスファチジルイノシトール(GPI)欠損症や発作性夜間ヘモグロビン尿症と言った難病を発症する。GPIの糖鎖部分の骨格は共通構造をしているが、側鎖によって多様性が生まれる。しかし側鎖の生合成機構は未解明であった。また、GPIはタンパク質に結合しないフリーの糖脂質としても存在することが知られているが、その生理的意義や病理的意義は不明であった。本研究の成果はこれらの課題に一定の進展をもたらした。