YBX1 regulates RNA polymerase III transcripts to prevent inflammation

Abstract

Significance Endogenous nucleic acids, including DNA and RNA, possess immunostimulatory features that, under normal cellular conditions, remain contained. Cellular stress, injury, or pathogenic infection releases endogenous nucleic acids to trigger innate immune responses, transforming them into damage-associated molecular patterns (DAMPs). Thus, cells allocate significant resources to shielding endogenous nucleic acids from the innate immune system. One such example includes the sequestration of noncoding RNAs by RNA-binding proteins (RBPs). Here, we report that a ubiquitous RBP, Y-box binding protein 1 (YBX1), prevents noncoding RNAs synthesized by RNA polymerase III from being recognized as DAMPs under cellular homeostasis. Together, our results uncover an underappreciated role for YBX1 as a guardian of noncoding RNA homeostasis, preventing inappropriate activation of innate immunity.