hnRNPM and ELAVL1 control type I interferon induction by promoting IRF3 phosphorylation downstream of both cGAS and RIG-I

Kirchhoff, A.; Herzner, A.-M.; Urban, C.; Piras, A.; Düster, R.; Wegner, J.; Grünewald, A.; Schlee-Guimaraes, T. M.; Ciupka, K.; Leka, P.; Bootz, R. J.; de Regt, A. K.; Kümmerer, B.; Honholt Christensen, M.; Schmidt, F. I.; Günther, C.; Kato, H.; Bartok, E.; Hartmann, G.; Geyer, M.; Pichlmair, A.; Schlee, M.

doi:10.1101/2023.06.23.545108

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bioRxiv · 10.1101/2023.06.23.545108

hnRNPM and ELAVL1 control type I interferon induction by promoting IRF3 phosphorylation downstream of both cGAS and RIG-I

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Abstract

RIG-I and cGAS are crucial sensors of viral nucleic acids and induce type I IFNs via TBK1/IKK and IRF3. Here, we have identified hnRNPM as a novel positive regulator of IRF3 phosphorylation and type I IFN induction downstream of both cGAS and RIG-I. Combining interactome analysis and genome editing, we further identified ELAVL1 as an immune-relevant interactor of hnRNPM. Depletion of hnRNPM or ELAVL1 impaired type I IFN induction by HSV-1 and SeV. In addition, we found that hnRNPM and ELAVL1 interact with TBK1 and NF-kB p65. Confocal microscopy revealed cytosolic and perinuclear interactions between hnRNPM, ELAVL1, and TBK1. To our knowledge, hnRNPM and ELAVL1 represent the first non-redundant signaling components merging the cGAS-STING and RIG-I-MAVS pathways, thus representing a novel platform that fuels antiviral defense.

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Kirchhoff, A., Herzner, A.-M., Urban, C., Piras, A., Düster, R., Wegner, J., Grünewald, A., Schlee-Guimaraes, T. M., Ciupka, K., Leka, P., Bootz, R. J., de Regt, A. K., Kümmerer, B., Honholt Christensen, M., Schmidt, F. I., Günther, C., Kato, H., Bartok, E., Hartmann, G., Geyer, M., Pichlmair, A., Schlee, M.. 2023-06-24. hnRNPM and ELAVL1 control type I interferon induction by promoting IRF3 phosphorylation downstream of both cGAS and RIG-I. https://doi.org/10.1101/2023.06.23.545108

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