The molecular mechanism underlying STING signalling

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03202
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43030:Functional biochemistry-related
• Research Institution: Tohoku University
• Principal Investigator: Kojiro Mukai 東北大学, 生命科学研究科, 助教 (90767633)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 自然免疫シグナル / 細胞内物質輸送 / 小胞体 / ゴルジ体 / エンドソーム / リソソーム

Outline of Final Research Achievements

The innate immune response is essential for efficient and rapid host defense against invading pathogens. The STING pathway is one of the major pathways of the innate immune response that responds to cytosolic microbial DNA from viruses or self-DNA from mitochondria/nuclei. In this study, we demonstrate the homeostatic regulation of STING at the resting state by the retrograde membrane traffic (Mukai et al., Nat Commun 2021). We also found that the STING signalling is terminated through ESCRT-dependent microautophagy of vesicles originating from recycling endosomes (Kuchitsu & Mukai et al., Nat Cell Biol 2023). These results suggest that the activity of STING is strictly regulated by membrane trafficking to prevent hyperactivation of innate immune signalling.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究では、定常状態において小胞体にSTINGを留める分子機構や、ゴルジ体で活性化した後のSTINGシグナルが収束する分子機構を明らかにし、それらの破綻が過剰な炎症応答に繋がることを見出した。これらの成果は、細胞内でのSTING経路の新規活性制御機構を明らかにしただけでなく、自己炎症性疾患の病態発症機序の解明やSTING特異的阻害剤の創薬研究にも貢献している。