Regulation of endogenous dsRNA: strategies for self-tolerance

Abstract Cells must continuously distinguish cellular-derived RNA from pathogenic RNA to mount effective antiviral responses while avoiding harmful autoinflammation. Cytoplasmic RNA-sensing receptors, including RIG-I-like receptors, PKR, OAS-RNase L and ZBP1, detect RNA primarily through molecular features such as structure (double- versus single-stranded), modification state and subcellular localization rather than sequence. While these are characteristics of viral nucleic acids, mammalian genomes generate abundant self-derived double-stranded RNA (dsRNA), including from transposable elements, antisense transcription and RNA processing intermediates, which exist in the cytoplasm. This review describes our current understanding of how cells achieve self-tolerance through the active regulation of endogenous RNA. These mechanisms comprise epigenetic silencing of repetitive elements, RNA modifications (such as A-to-I editing and m6A), precise splicing, regulated nuclear export and decay, circRNA buffering, protein shielding and dedicated RNA degradation pathways. Insights from rare inherited monogenic interferonopathies and murine models illustrate how perturbations in these pathways lead to inappropriate activation of cytoplasmic RNA sensors and inflammatory disease when cellular dsRNA is mistakenly recognized as non-self. We highlight how dysregulated dsRNA homeostasis contributes to common autoimmune and neuroinflammatory disorders. Understanding how cells regulate endogenous dsRNA is crucial for defining disease mechanisms and developing new therapeutic strategies.