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bioRxiv · 10.1101/2024.04.01.587645

MATRIN3 deficiency triggers autoinflammation via cGAS-STING activation

Islam, Z.·Polash, A.·Suzawa, M.·Chim, B.·Kuhn, S.·Sultana, S.·Cutrona, N.·Smith, P. T.·Kabat, J.·Ganesan, S.·Foroushani, A.·Hafner, M.·Muljo, S. A.
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Abstract

Interferon-stimulated genes (ISGs) comprise a program of immune effectors important for host immune defense. When uncontrolled, ISGs play a central role in interferonopathies and other inflammatory diseases. The mechanisms responsible for turning on ISGs are not completely known. By investigating MATRIN3 (MATR3), a nuclear RNA-binding protein mutated in familial ALS, we found that perturbing MATR3 results in elevated expression of ISGs. Using an integrative approach, we elucidate a pathway that leads to activation of cGAS-STING. This outlines a plausible mechanism for pathogenesis in a subset of ALS, and suggests new diagnostic and therapeutic approaches for this fatal disease. One-Sentence SummaryMis-splicing of Tudor Domain Containing 3 (TDRD3) in the absence of MATR3 unleashes R-loops and interferon-stimulated genes.

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Islam, Z., Polash, A., Suzawa, M., Chim, B., Kuhn, S., Sultana, S., Cutrona, N., Smith, P. T., Kabat, J., Ganesan, S., Foroushani, A., Hafner, M., Muljo, S. A.. 2024-04-02. MATRIN3 deficiency triggers autoinflammation via cGAS-STING activation. https://doi.org/10.1101/2024.04.01.587645

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