Identification of proteins involved in the transbilayer movement of sphingomyelin

2022 Fiscal Year Final Research Report

• Project/Area Number: 18K06677
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Abe Mitsuhiro 国立研究開発法人理化学研究所, 開拓研究本部, 専任研究員 (90415068)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Keywords: スフィンゴ脂質 / 脂質ラフト / スフィンゴミエリン / フリップ / フリッパーゼ / 細胞膜 / PMP2 / PI(4,5)P2

Outline of Final Research Achievements

Sphingomyelin (SM) is a mammalian lipid mainly distributed in the outer leaflet of the plasma membrane (PM). We show that peripheral myelin protein 2 (PMP2) can localize at the PM and controls the transbilayer distribution of SM. Genetic screening with genome-wide small hairpin RNA libraries identifies PMP2 as a protein involved in the transbilayer movement of SM. A biochemical assay demonstrates that PMP2 is a phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-binding protein. PMP2 induces the tubulation of model membranes in a PI(4,5)P2-dependent manner, accompanied by the modification of the transbilayer membrane distribution of lipids. In the PM of the PMP2-overexpressing cells, inner-leaflet SM is increased whereas outer-leaflet SM is reduced. PMP2 is a causative protein of Charcot-Marie-Tooth disease (CMT). A mutation in PMP2 associated with CMT increases its affinity for PI(4,5)P2 inducing membrane tubulation and the subsequent transbilayer movement of lipids.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

グリセロ脂質に関しては，P4-ATPaseファミリーに属するflippaseによって，細胞膜における非対称性が生み出される。グリセロ脂質の非対称性は，アポトーシス，細胞膜の曲率変化，小胞輸送，細胞膜極性にとって重要な働きを担っていること報告されている。一方，SMを含めスフィンゴ脂質に関しては，非対称性を生み出す分子機構，およびその生理的意義はほとんどわかっていなかった。今回見出したPMP2によるSMのflipは，スフィンゴ脂質のflipの初めての例である。今後，SMの非対称性を変えた変異細胞を用いて，ウイルス感染や末梢神経疾患に対する薬剤の開発など，応用が期待される。