Immune sensing of synthetic, bacterial and protozoan RNA by TLR8 requires coordinated processing of RNA substrates by RNaseT2 and RNase2

Abstract Human TLR8 is an essential sensor of bacterial RNA which induces proinflammatory and Th1 cytokines. Crystallography revealed that TLR8 binds both uridine and short single-stranded RNA, but the RNases that process the RNA are still unknown. Herein, we demonstrate that two endosomal endoribon...

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Published in:	The Journal of immunology (1950) Vol. 204; no. 1_Supplement; pp. 226 - 226.30
Main Authors:	Bartok, Eva Sarah, Ostendorf, Thomas, Zillinger, Thomas, Andryka, Katarzyna, Guimaraes, Thais Marina, Schmitz, Saskia, Marx, Samira, Bayrak, Kübra, Linke, Rebecca, Salgert, Sarah, Grasser, Tatjana, Baersachs, Sonja, Hübner, Marc, Soltesz, Leon, Kettwig, Matthias, Nastaly, Maximilian, Roehl, Ingo, Henneke, Marco, Barchet, Winfried, Gärtner, Jutta, Schlee, Martin, Hartmann, Gunther
Format:	Journal Article
Language:	English
Published:	01-05-2020
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Summary:	Abstract Human TLR8 is an essential sensor of bacterial RNA which induces proinflammatory and Th1 cytokines. Crystallography revealed that TLR8 binds both uridine and short single-stranded RNA, but the RNases that process the RNA are still unknown. Herein, we demonstrate that two endosomal endoribonucleases, RNaseT2 and RNase2, can process RNA for TLR8 recognition. In the endosome, RNase2 and -T2 act synergistically to release uridine from oligoribonucleotides, with RNaseT2 cleaving preferentially before and RNase2 after uridines. Live bacteria, P. falciparum-infected red blood cells, purified pathogen RNA, and synthetic ligands all required RNase processing for TLR8 activation, and uridine supplementation restored RNA recognition in RNASE2−/− or RNASET2−/− but not double knockout cells. Strikingly, peripheral blood mononuclear cells from RNaseT2 hypomorphic patients did not respond to bacterial RNA but did to small-molecule TLR8 agonists. Our data provide a novel insight into TLR8 activation and its differences between cell types and species.
ISSN:	0022-1767 1550-6606
DOI:	10.4049/jimmunol.204.Supp.226.30