PUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation [Polysome profiling]

Pseudouridine (Y) is the most widespread RNA modification type on cellular RNAs and is dynamically catalyzed by a family of Y synthases (PUSes) in response to pathophysiological cues. PUS10 has been previously shown to regulate miRNA biogenesis in addition to modifying tRNAs, however its role in adapting gene expression to stress remains elusive. Here, we establish a novel role for PUS10 as a regulator of LTR retrotransposon-driven inflammatory response. Using Pus10 KO mice, we demonstrate that Pus10 depletion leads to upregulation of interferon-stimulated genes (ISGs) and increased resistance to viral infection in vitro and in vivo. Mechanistically, PUS10 regulates a subset of 5’-derived tRNA (tdR) fragment, 5’ tdR Gly-GCC, that via targeting specific LTR retroelements modulates RNA-DNA hybrids accumulation and cGAS/STING/IRF3 pathway. Importantly, reduced PUS10 activity correlate with chronic autoimmune conditions, pinpointing PUS10 as a potential contributor to human immune regulation.