Significance of membrane microdomain Lipoquality in the regulation of inflammatory signals

2019 Fiscal Year Final Research Report

• Project Area: Quality of lipids in biological systems
• Project/Area Number: 15H05903
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Toyama-Sorimachi Noriko 国立研究開発法人国立国際医療研究センター, その他部局等, 分子炎症制御プロジェクト長 (30217468)
• Co-Investigator(Kenkyū-buntansha): 田口 友彦 東北大学, 生命科学研究科, 教授 (10300881)
• Project Period (FY): 2015-06-29 – 2020-03-31
• Keywords: 膜脂質ドメイン / 炎症 / シグナル伝達 / リポクオリティ

Outline of Final Research Achievements

Membrane lipid bilayer plays important functions not only as physical barrier of cells/organelles but also as signal platforms. We here investigated the role of lipid microdomains in inflammatory responses using newly established probes which specifically bind to phosphatidyl serine or sphingomyelin (SM). We found that SM was detected in the cytosolic leave of membranes of trans-golgi network, recycling endosomes and lysosomes. SM-enriched membrane domains in trans-golgi network recruited STING and TBK1, and mediated STING-dependent type I Interferon productions. STING palmitoylation was critical for its localization to SM-rich golgi membrane. We also found that SM-rich domain in lysosomes was constituted depending on MHC class I and its cis-interacting C-type lectin, and this domain played important role for macrophage phagocytosis. Our results revealed that SM-enriched membrane microdomains in organelle provide important platforms for transmitting various inflammatory signals.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

エネルギー源、メディエーターとしての役割についての理解に比し、膜としての脂質の機能解析の現状は、ツールも少なく困難が多い。そのような状況下で、本研究は新たな脂質プローブを用い、細胞機能発現における“膜脂質ドメインの質”の重要性を明らかにしたものである。同時に、膜受容体とシグナル分子という、タンパク質を中心として理解が進められてきた炎症応答に、膜脂質ドメインが担う細胞内の空間的炎症制御のメカニズムが明らかになったという点において、新たな炎症制御概念を樹立するとともに、治療戦略の作出に新たな可能性をもたらした。