Complex formation of sphingomyelin synthase with glucosylceramide synthase increases sphingomyelin and decreases glucosylceramide levels

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06635
• 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: Teikyo University
• Principal Investigator: Hayashi Yasuhiro 帝京大学, 薬学部, 講師 (70582857)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 脂質代謝酵素

Outline of Final Research Achievements

Sphingomyelin synthase 1 (SMS1) and glucosylceramide synthase (GlcT) are key enzymes that catalyze the conversion of ceramide (Cer) to sphingomyelin (SM) and glucosylceramide (GlcCer), respectively. GlcCer synthesis has been postulated to occur mainly in cis-Golgi, and SM synthesis is thought to occur in medial/trans-Golgi; however, SMS1 and GlcT are known to partially colocalize in cisternae, especially in medial/trans-Golgi. Here, we report that SMS1 and GlcT can form a heteromeric complex, in which the N terminus of SMS1 and the C terminus of GlcT are in close proximity. Deletion of the N-terminal sterile alpha motif of SMS1 reduced the stability of the SMS1/GlcT complex, resulting in a significant reduction in SM synthesis in vivo. In contrast, chemical-induced heterodimerization augmented SMS1 activity, depending on an increase in the amount and stability of the complex. These results suggest that formation of the SMS1/GlcT heteromeric complex increases SM synthesis.

Free Research Field

脂質代謝酵素

Academic Significance and Societal Importance of the Research Achievements

近年、SMはメタボリックシンドロームへの関与のみならず、機能性食品素材としても注目されている。このことは、SM量は生体内で適切にコントロールされるべきであり、体内でのSM量の過剰な産生および減少は、私たちの健康寿命を縮めることを示唆している。本研究は、SM産生の制御のメカニズムの一部を解明したという学術的な発見にとどまらず、SMのメタボリックシンドロームへの関与を解明する研究基盤へと繋がっていくことが期待される。