自然免疫の活性化: パズルの重要なピースが判明(Activation of innate immunity: Important piece of the puzzle identified)

2024-05-03

2024-05-02 ミュンヘン大学(LMU)

トール様受容体7(TLR7)は、免疫系の樹状細胞にあり、ウイルスに対する自然防御に重要な役割を果たします。TLR7は一本鎖ウイルスRNAや外来RNAを認識し、炎症性メディエーターを放出します。しかし、この受容体の機能異常は自己免疫疾患の原因となります。ミュンヘン大学の研究者が、TLR7の活性化メカニズムに関する詳細な理解を得ました。研究によると、TLR7のRNA認識にはエンドヌクレアーゼRNase T2とエキソヌクレアーゼPLD3およびPLD4の活性が必要であり、これらは炎症を調整するバランスを持っています。この知見は、炎症制御の新たな標的として期待されています。

<関連情報>

リソソームのエンドヌクレアーゼRNase T2とPLDエキソヌクレアーゼが、TLR7活性化のためのRNAリガンドを協同で生成(Lysosomal endonuclease RNase T2 and PLD exonucleases cooperatively generate RNA ligands for TLR7 activation)

Marleen Bérouti,Katja Lammens,Matthias Heiss,…,Thomas Carell,Karl-Peter Hopfner,Veit Hornung
Immunity Published:May 01, 2024
DOI:https://doi.org/10.1016/j.immuni.2024.04.010

Highlights

•RNase T2 and PLD exonucleases process RNA upstream of TLR7

•PLD exonucleases release terminal 2′,3′-cyclic GMPs to engage TLR7 pocket 1

•PLD enzymes are also critical to generate RNA fragments for TLR7 pocket 2

•PLDs dimer formation is needed for RNA substrate processing

Summary

Toll-like receptor 7 (TLR7) is essential for recognition of RNA viruses and initiation of antiviral immunity. TLR7 contains two ligand-binding pockets that recognize different RNA degradation products: pocket 1 recognizes guanosine, while pocket 2 coordinates pyrimidine-rich RNA fragments. We found that the endonuclease RNase T2, along with 5′ exonucleases PLD3 and PLD4, collaboratively generate the ligands for TLR7. Specifically, RNase T2 generated guanosine 2′,3′-cyclic monophosphate-terminated RNA fragments. PLD exonuclease activity further released the terminal 2′,3′-cyclic guanosine monophosphate (2′,3′-cGMP) to engage pocket 1 and was also needed to generate RNA fragments for pocket 2. Loss-of-function studies in cell lines and primary cells confirmed the critical requirement for PLD activity. Biochemical and structural studies showed that PLD enzymes form homodimers with two ligand-binding sites important for activity. Previously identified disease-associated PLD mutants failed to form stable dimers. Together, our data provide a mechanistic basis for the detection of RNA fragments by TLR7.