YBX1 regulates RNA polymerase III transcripts to prevent inflammation

Tolerance of endogenous nucleic acids is crucial for cellular homeostasis and when perturbed can lead to immune dysregulation. RNA-binding proteins (RBPs) bind, modify, and compartmentalize endogenous RNAs to prevent their recognition by the innate immune system. We found that loss of a highly abundant RBP, the cold shock domain containing Y-box binding protein 1 (YBX1), results in the spontaneous induction of an IL6/STAT3 inflammatory response and the upregulation of interferon-stimulated genes. A meta-analysis of other studies reveals that the depletion of YBX1 orthologs and paralogs results in a similar proinflammatory gene signature, suggesting a conserved role of Y-box proteins in maintaining innate immune homeostasis. Among RNAs that interact with YBX1, we tested whether endogenous RNA polymerase III (RNAP III) transcripts stimulate innate immune signaling when YBX1 is depleted. We demonstrate that the inflammatory responses induced by the loss of YBX1 are abrogated by inhibiting RNAP III transcription and RIG-I signaling. Hence, we hypothesize that by regulating RNAP III transcripts, YBX1 prevents their recognition by the innate immune system, uncovering a role of this RBP in maintaining cellular homeostasis and tolerance to endogenous RNAs. The conservation of this phenotype across YBX1 orthologs and paralogs argues that RNA shielding by cold shock domain proteins represents an evolutionarily conserved solution to the problem of endogenous RNA immunogenicity.