Immune Sensing of Synthetic, Bacterial, and Protozoan RNA by Toll-like Receptor 8 Requires Coordinated Processing by RNase T2 and RNase 2

被引：87

作者：

Ostendorf, Thomas ^{[1
]}

Zillinger, Thomas ^{[1
]}

Andryka, Katarzyna ^{[1
]}

Schlee-Guimaraes, Thais Marina ^{[1
]}

Schmitz, Saskia ^{[1
]}

Marx, Samira ^{[1
]}

Bayrak, Kubra ^{[1
]}

Linke, Rebecca ^{[1
]}

Salgert, Sarah ^{[1
]}

Wegner, Julia ^{[1
]}

Grasser, Tatjana ^{[2
]}

Bauersachs, Sonja ^{[2
]}

Soltesz, Leon ^{[1
]}

Huebner, Marc P. ^{[3
]}

Nastaly, Maximilian ^{[1
]}

Coch, Christoph ^{[1
,4
]}

Kettwig, Matthias ^{[5
]}

Roehl, Ingo ^{[2
]}

Henneke, Marco ^{[5
]}

Hoerauf, Achim ^{[3
,6
]}

Barchet, Winfried ^{[1
,6
]}

Gaertner, Jutta ^{[5
]}

Schlee, Martin ^{[1
]}

Hartmann, Gunther ^{[1
,6
]}

Bartok, Eva ^{[1
]}

机构：

[1] Univ Hosp Bonn, Dept Clin Chem & Clin Pharmacol, Bonn, Germany

[2] Axolabs GmbH, Fritz Hornschuch Str 9, D-95326 Kulmbach, Germany

[3] Univ Hosp Bonn, IMMIP, Bonn, Germany

[4] Miltenyi Biotech, Biomed Div, Bergisch Gladbach, Germany

[5] Georg August Univ, Univ Med Ctr Gottingen, Div Pediat Neurol, Dept Pediat & Adolescent Med, Gottingen, Germany

[6] German Ctr Infect Res DZIF, Partner Site Bonn Cologne, Cologne, Germany

来源：

IMMUNITY | 2020年 / 52卷 / 04期

关键词：

CYSTIC LEUKOENCEPHALOPATHY; STRANDED-RNA; TLR8; RECOGNITION; RIBONUCLEASES; FAMILY; EVOLUTION; MONOCYTES; ALPHA; CELLS;

D O I：

10.1016/j.immuni.2020.03.009

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Human toll-like receptor 8 (TLR8) activation induces a potent T helper-1 (Th1) cell response critical for defense against intracellular pathogens, including protozoa. The receptor harbors two distinct binding sites, uridine and di- and/or trinucleotides, but the RNases upstream of TLR8 remain poorly characterized. We identified two endolysosomal endoribonucleases, RNase T2 and RNase 2, that act synergistically to release uridine from oligoribonucleotides. RNase T2 cleaves preferentially before, and RNase 2 after, uridines. Live bacteria, P. falciparum-infected red blood cells, purified pathogen RNA, and synthetic oligoribonucleotides all required RNase 2 and T2 processing to activate TLR8. Uridine supplementation restored RNA recognition in RNASE2(-/-) or RNASET2(-/-) but not RNASE2(-/-) RNASET2(-/-) cells. Primary immune cells from RNase T2-hypomorphic patients lacked a response to bacterial RNA but responded robustly to small-molecule TLR8 ligands. Our data identify an essential function of RNase T2 and RNase 2 upstream of TLR8 and provide insight into TLR8 activation.

引用

页码：591 / +

页数：21

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