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1.
Immunity ; 57(7): 1482-1496.e8, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38697119

RESUMO

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.


Assuntos
Endorribonucleases , Receptor 7 Toll-Like , Receptor 7 Toll-Like/metabolismo , Receptor 7 Toll-Like/genética , Humanos , Endorribonucleases/metabolismo , Ligantes , Fosfolipase D/metabolismo , Fosfolipase D/genética , RNA/metabolismo , Células HEK293 , Lisossomos/metabolismo , Animais , Exonucleases/metabolismo , Camundongos , Sítios de Ligação
2.
Cell ; 179(6): 1264-1275.e13, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31778653

RESUMO

TLR8 is among the highest-expressed pattern-recognition receptors in the human myeloid compartment, yet its mode of action is poorly understood. TLR8 engages two distinct ligand binding sites to sense RNA degradation products, although it remains unclear how these ligands are formed in cellulo in the context of complex RNA molecule sensing. Here, we identified the lysosomal endoribonuclease RNase T2 as a non-redundant upstream component of TLR8-dependent RNA recognition. RNase T2 activity is required for rendering complex single-stranded, exogenous RNA molecules detectable for TLR8. This is due to RNase T2's preferential cleavage of single-stranded RNA molecules between purine and uridine residues, which critically contributes to the supply of catabolic uridine and the generation of purine-2',3'-cyclophosphate-terminated oligoribonucleotides. Thus-generated molecules constitute agonistic ligands for the first and second binding pocket of TLR8. Together, these results establish the identity and origin of the RNA-derived molecular pattern sensed by TLR8.


Assuntos
Endorribonucleases/metabolismo , Proteólise , Receptor 8 Toll-Like/metabolismo , Motivos de Aminoácidos , Sequência de Bases , Linhagem Celular , Endorribonucleases/deficiência , Humanos , Modelos Moleculares , Monócitos/metabolismo , Células Mieloides/metabolismo , Isótopos de Nitrogênio , Oligonucleotídeos/metabolismo , Purinas/metabolismo , RNA/metabolismo , Staphylococcus aureus/metabolismo , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/agonistas , Receptor 8 Toll-Like/química , Uridina/metabolismo
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