Regulation of endogenous dsRNA: strategies for self-tolerance
- 1Centre for Innate Immunity and Infectious Disease, Hudson Institute of Medical Research 1 , Clayton, Victoria, Australia
- 2Monash University—Clayton Campus 2 , Melbourne, Victoria, Australia
- 3Molecular Sciences Division, Walter and Eliza Hall Institute of Medical Research 3 , Melbourne, Victoria, Australia
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.
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BibTeX
@article{heraudfarlow2026regulation,
title = {{Regulation of endogenous dsRNA: strategies for self-tolerance}},
author = {Jacki Heraud-Farlow and Yu-Pei Chan and Sophia Davidson and Carl Walkley},
journal = {Open Biology},
year = {2026},
month = nov,
doi = {10.1098/rsob.260111},
url = {https://royalsocietypublishing.org/rsob/article/16/11/260111/484057/Regulation-of-endogenous-dsRNA-strategies-for-self},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Regulation of endogenous dsRNA: strategies for self-tolerance
AU - Jacki Heraud-Farlow
AU - Yu-Pei Chan
AU - Sophia Davidson
AU - Carl Walkley
PY - 2026
DA - 2026/11/04
JO - Open Biology
DO - 10.1098/rsob.260111
UR - https://royalsocietypublishing.org/rsob/article/16/11/260111/484057/Regulation-of-endogenous-dsRNA-strategies-for-self
AB - 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.
SN - 2046-2441
ER -