Mitochondria-derived dsRNA-induced stress granules promote IRF3-mediated fibrotic responses

Travers, J.; Huang, E.; McMullen, M. R.; Wu, J.; Cajigas-Du Ross, C. K.; Paouri, E.; Davalos, D.; Pathak, V.; Rotroff, D. M.; Nagy, L. E.

doi:10.1101/2025.05.14.654103

bioRxiv · 10.1101/2025.05.14.654103

Mitochondria-derived dsRNA-induced stress granules promote IRF3-mediated fibrotic responses

Travers, J.·Huang, E.·McMullen, M. R.·Wu, J.·Cajigas-Du Ross, C. K.·Paouri, E.·Davalos, D.·Pathak, V.·Rotroff, D. M.·Nagy, L. E.

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Abstract

Nucleic acid-induced activation of the anti-viral transcription factor interferon regulatory factor 3 (IRF3) promotes transforming growth factor-beta (TGF{beta})-induced fibrotic responses of hepatic stellate cells in vitro. Herein, we identified molecular mechanisms underlying TGF{beta}-induced IRF3 activation. Gene silencing of IRF3 with short interfering RNA (siRNA) in LX2 human hepatic stellate cells decreased TGF{beta}-induced fibrotic responses. An unbiased proteomic analysis of homeostatic IRF3-interacting proteins revealed striking enrichment in cytoplasmic stress granule components, including G3BP stress granule assembly factor 1 (G3BP1), G3BP2, and cell cycle associated protein 1 (CAPRIN1). TGF{beta} induced cytoplasmic accumulation of mitochondria-derived double-stranded RNA (mt-dsRNA) and assembly of IRF3-containing stress granules. Finally, blockade of G3BP1 activity or depletion of mt-dsRNA decreased TGF{beta}-induced fibrotic responses. Collectively, these findings identify a novel TGF{beta}-mt-dsRNA-stress granule axis in hepatic stellate cells that promotes IRF3-mediated fibrotic responses and potentially implicate cytoplasmic stress granules as a global regulator of fibrosis.

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Travers, J., Huang, E., McMullen, M. R., Wu, J., Cajigas-Du Ross, C. K., Paouri, E., Davalos, D., Pathak, V., Rotroff, D. M., Nagy, L. E.. 2025-05-15. Mitochondria-derived dsRNA-induced stress granules promote IRF3-mediated fibrotic responses. https://doi.org/10.1101/2025.05.14.654103

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