A noncanonical function of Dicer fuels self-dsRNA-driven inflammation
- 1Leiden University Medical Center
Abstract
Self-derived double-stranded RNAs (self-dsRNAs) can drive autoinflammation, but how structurally constrained self-dsRNAs become immunostimulatory remains unclear. We identify a noncanonical role for Dicer and a broad requirement for LGP2 in this process. Dicer is required for responses to self-dsRNAs, but not exogenous dsRNAs, that arise from defects in RNA editing, splicing, epigenetic silencing, or mitochondrial RNA degradation in multiple cell types, including a human stem cell-derived model of neuroinflammation. Independently of microRNA biogenesis, Dicer promotes activation of MDA5, PKR, and OAS-RNase L. Dicer binds immunostimulatory dsRNAs and uses its catalytic activity to generate shorter duplexes with accessible ends that are available for LGP2 end-binding, enabling MDA5 filament assembly. Thus, Dicer converts short, structurally constrained self-dsRNAs into inflammatory ligands, thereby facilitating their recognition as danger-associated signals.
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BibTeX
@misc{haar2026noncanonical,
title = {{A noncanonical function of Dicer fuels self-dsRNA-driven inflammation}},
author = {L. R. ter Haar and S. de Lange and D. Gravekamp and A. R. Kooij and J. W. de Wolf and Y. Asschert and T. Oosenbrug and M. W. Paul and P. A. van Veelen and W. M. C. van Roon-Mom and H. Mei and A. G. Van der Veen},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.29.761885},
url = {https://www.biorxiv.org/content/10.64898/2026.10.29.761885v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A noncanonical function of Dicer fuels self-dsRNA-driven inflammation
AU - L. R. ter Haar
AU - S. de Lange
AU - D. Gravekamp
AU - A. R. Kooij
AU - J. W. de Wolf
AU - Y. Asschert
AU - T. Oosenbrug
AU - M. W. Paul
AU - P. A. van Veelen
AU - W. M. C. van Roon-Mom
AU - H. Mei
AU - A. G. Van der Veen
PY - 2026
DA - 2026/10/29
PB - bioRxiv
DO - 10.64898/2026.10.29.761885
UR - https://www.biorxiv.org/content/10.64898/2026.10.29.761885v1
AB - Self-derived double-stranded RNAs (self-dsRNAs) can drive autoinflammation, but how structurally constrained self-dsRNAs become immunostimulatory remains unclear. We identify a noncanonical role for Dicer and a broad requirement for LGP2 in this process. Dicer is required for responses to self-dsRNAs, but not exogenous dsRNAs, that arise from defects in RNA editing, splicing, epigenetic silencing, or mitochondrial RNA degradation in multiple cell types, including a human stem cell-derived model of neuroinflammation. Independently of microRNA biogenesis, Dicer promotes activation of MDA5, PKR, and OAS-RNase L. Dicer binds immunostimulatory dsRNAs and uses its catalytic activity to generate shorter duplexes with accessible ends that are available for LGP2 end-binding, enabling MDA5 filament assembly. Thus, Dicer converts short, structurally constrained self-dsRNAs into inflammatory ligands, thereby facilitating their recognition as danger-associated signals.
ER -