SLIRP mediates nuclear-mitochondrial communication during antiviral signaling to promote robust interferon response

Ku, D.; Yang, Y.; Park, Y.; Jang, D.; Lee, K.; Lee, N.; Lee, Y.-k.; Lee, J.; Han, Y. B.; Jang, S.; Choi, S. R.; Ha, Y.-J.; Choi, Y. S.; Jeong, W.-J.; Lee, Y. J.; Lee, K. J.; Cha, S.; Kim, Y.

doi:10.1101/2024.03.28.587146

bioRxiv · 10.1101/2024.03.28.587146

SLIRP mediates nuclear-mitochondrial communication during antiviral signaling to promote robust interferon response

Ku, D.·Yang, Y.·Park, Y.·Jang, D.·Lee, K.·Lee, N.·Lee, Y.-k.·Lee, J.·Han, Y. B.·Jang, S.·Choi, S. R.·Ha, Y.-J.·Choi, Y. S.·Jeong, W.-J.·Lee, Y. J.·Lee, K. J.·Cha, S.·Kim, Y.

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Abstract

The abnormal innate immune response is a prominent feature underlying autoimmune diseases. One emerging factor that can trigger dysregulated immune activation is cytosolic mitochondrial double-stranded RNAs (mt-dsRNAs). However, the mechanism by which mt-dsRNAs stimulate immune responses remains poorly understood. Here, we discover SRA stem-loop interacting RNA binding protein (SLIRP) as a key amplifier of mt-dsRNA-triggered antiviral signals. In autoimmune diseases, SLIRP is commonly upregulated, and targeted knockdown of SLIRP dampens the interferon response. We find that the activation of melanoma differentiation-associated gene 5 (MDA5) by exogenous dsRNAs upregulates SLIRP, which then stabilizes mt-dsRNAs and promotes their cytosolic release to activate MDA5 further, augmenting the interferon response. Furthermore, the downregulation of SLIRP partially rescues the abnormal interferon-stimulated gene expression in autoimmune patients primary cells and makes cells vulnerable to certain viral infections. Our study unveils SLIRP as a pivotal mediator of interferon response through positive feedback amplification of antiviral signaling.

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Ku, D., Yang, Y., Park, Y., Jang, D., Lee, K., Lee, N., Lee, Y.-k., Lee, J., Han, Y. B., Jang, S., Choi, S. R., Ha, Y.-J., Choi, Y. S., Jeong, W.-J., Lee, Y. J., Lee, K. J., Cha, S., Kim, Y.. 2024-04-02. SLIRP mediates nuclear-mitochondrial communication during antiviral signaling to promote robust interferon response. https://doi.org/10.1101/2024.03.28.587146

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