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.

中文翻译：

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Toll样受体8对合成，细菌和原生动物RNA的免疫感应需要RNase T2和RNase 2的协同处理。

人类通行费样受体8（TLR8）激活诱导有效的T辅助1（Th1）细胞应答，对防御细胞内病原体（包括原生动物）至关重要。该受体具有两个不同的结合位点，尿苷和二核苷酸和/或三核苷酸，但在TLR8上游的RNase仍然很难鉴定。我们确定了两个溶酶体内核糖核酸酶，RNase T2和RNase 2，协同发挥作用，从寡核糖核苷酸释放尿苷。RNase T2在尿苷之前优先裂解，RNase 2在尿苷之后裂解。活细菌，恶性疟原虫感染的红细胞，纯化的病原体RNA和合成的寡核糖核苷酸都需要RNase 2和T2处理才能激活TLR8。补充尿苷可恢复RNASE2-/-或RNASET2-/-中的RNA识别，但不能恢复RNASE2-/-RNASET2-/-细胞中的RNA识别。来自RNase T2亚型患者的原代免疫细胞对细菌RNA缺乏反应，但对小分子TLR8配体有强烈反应。我们的数据确定了TLR8上游的RNase T2和RNase 2的基本功能，并提供了对TLR8激活的了解。