Cell and Molecular mechanisms underlying the interaction between the innate immune system and metabolism in lysosomes

2020 Fiscal Year Final Research Report

• Project/Area Number: 16H06388
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Immunology
• Research Institution: The University of Tokyo
• Principal Investigator: MIYAKE Kensuke 東京大学, 医科学研究所, 教授 (60229812)
• Project Period (FY): 2016-05-31 – 2021-03-31
• Keywords: 自然免疫

Outline of Final Research Achievements

The lysosome is the site for nucleic acid (NA) metabolism, NA-sensing by Toll-like receptors (TLRs), and metabolite-sensing by mTORC1. We focused on the crosstalk among these processes. TLR7 and TLR3 induced lysosomal anterograde trafficking in a manner dependent on Arl8b or Rab7a, respectively. Such lysosomal trafficking enabled type I interferon induction through TLR interaction with mTORC1. We also studied the role of RNaseT2, the lysosomal RNase, in activation of RNA-sensing TLRs. RNase T2 negatively and positively regulated RNA-sensing TLRs probably through their ligand degradation or generation, respectively. These results demonstrate that NA metabolism and mTORC1 control NA-sensing TLRs. Dysregulation of the control causes human diseases such as histiocytosis.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

単なる老廃物処理場と考えられてきたリソソームが、細胞の代謝状態を監視し代謝異常に対する細胞応答を決定する「司令塔」としても機能していることが分かりつつある。本研究では、リソソームに局在する核酸特異的TLRと代謝産物、あるいはmTORC1との相互作用に注目し、核酸特異的TLRがリソソームでの核酸代謝異常に対する細胞応答の誘導に関与することを示した。この結果は、リソソームの機能解明に貢献することが期待される。