A noncanonical function of Dicer fuels self-dsRNA-driven inflammation

ter Haar, L. R.; de Lange, S.; Gravekamp, D.; Kooij, A. R.; de Wolf, J. W.; Asschert, Y.; Oosenbrug, T.; Paul, M. W.; van Veelen, P. A.; van Roon-Mom, W. M. C.; Mei, H.; Van der Veen, A. G.

doi:10.64898/2026.10.29.761885

bioRxiv · 10.64898/2026.10.29.761885

A noncanonical function of Dicer fuels self-dsRNA-driven inflammation

ter Haar, L. R.·de Lange, S.·Gravekamp, D.·Kooij, A. R.·de Wolf, J. W.·Asschert, Y.·Oosenbrug, T.·Paul, M. W.·van Veelen, P. A.·van Roon-Mom, W. M. C.·Mei, H.·Van der Veen, A. G.

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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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ter Haar, L. R., de Lange, S., Gravekamp, D., Kooij, A. R., de Wolf, J. W., Asschert, Y., Oosenbrug, T., Paul, M. W., van Veelen, P. A., van Roon-Mom, W. M. C., Mei, H., Van der Veen, A. G.. 2026-11-03. A noncanonical function of Dicer fuels self-dsRNA-driven inflammation. https://doi.org/10.64898/2026.10.29.761885

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