Lysosomal endonuclease RNase T2 and PLD exonucleases cooperatively generate RNA ligands for TLR7 activation

Bérouti, Marleen; Lammens, Katja; Heiss, Matthias; Hansbauer, Larissa; Bauernfried, Stefan; Stöckl, Jan; Pinci, Francesca; Piseddu, Ignazio; Greulich, Wilhelm; Wang, Meiyue; Jung, Christophe; Fröhlich, Thomas; Carell, Thomas ; Hopfner, Karl-Peter und Hornung, Veit (2024): Lysosomal endonuclease RNase T2 and PLD exonucleases cooperatively generate RNA ligands for TLR7 activation. In: Immunity, Bd. 57, Nr. 7: S. 1482-1496

Abstract

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department Biochemie ; Chemie und Pharmazie > Department Chemie ; Chemie und Pharmazie > GenZentrum ; Medizin > Klinikum der LMU München > Medizinische Klinik und Poliklinik II (Gastroenterologie, Hepatologie)
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 10747613
• Sprache: Englisch