PubReading [31] - TLR8 Is a Sensor of RNase T2 Degradation Products - W. Greulic, T. Carell, V. Hornung et al.

<p><strong>TLR8</strong> 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 <strong>RNA degradation products</strong>, 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 <strong>RNase T2</strong>’s preferential <strong>cleavage of single-stranded RNA molecule</strong>s between purine and uridine residues, which critically contributes to the supply of catabolic uridine and the generation of purine-<strong>2',3'-cyclophosphate</strong>-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. - doi.org/10.1016/j.cell.2019.11.001 - 2019</p>