RNA-binding proteins hnRNPM and ELAVL1 promote type-I interferon induction downstream of the nucleic acid sensors cGAS and RIG-I

  • EMBO J. 2025 Feb;44(3):824-853. doi: 10.1038/s44318-024-00331-x.
Alexander Kirchhoff  1 ,  Anna-Maria Herzner  2  3 ,  Christian Urban  4 ,  Antonio Piras  4 ,  Robert Düster  5 ,  Julia Mahlberg  2 ,  Agathe Grünewald  2 ,  Thais M Schlee-Guimarães  2 ,  Katrin Ciupka  2 ,  Petro Leka  6 ,  Robert J Bootz  2 ,  Christina Wallerath  2 ,  Charlotte Hunkler  2 ,  Ann Kristin de Regt  2 ,  Beate M Kümmerer  7  8 ,  Maria Hønholt Christensen  6 ,  Florian I Schmidt  6 ,  Min Ae Lee-Kirsch  9  10 ,  Claudia Günther  11 ,  Hiroki Kato  12 ,  Eva Bartok  2  13  14 ,  Gunther Hartmann  2 ,  Matthias Geyer  5 ,  Andreas Pichlmair  4  15 ,  Martin Schlee  16
Affiliations
  • 1. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany. [email protected].
  • 2. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
  • 3. Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany.
  • 4. Institute of Virology, Technical University of Munich, School of Medicine, Munich, Germany.
  • 5. Institute of Structural Biology, University Hospital Bonn, Bonn, Germany.
  • 6. Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany.
  • 7. Institute of Virology, University Hospital Bonn, Bonn, Germany.
  • 8. German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, 53127, Bonn, Germany.
  • 9. Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • 10. German Center for Child and Adolescent Health (DZKJ), partner site Leipzig/Dresden, Dresden, Germany.
  • 11. Department of Dermatology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • 12. Institute of Cardiovascular Immunology, University Hospital Bonn, Bonn, Germany.
  • 13. Unit of Experimental Immunology, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
  • 14. Institute of Experimental Haematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany.
  • 15. German Center for Infection Research (DZIF), Partner Site Munich, 81675, Munich, Germany.
  • 16. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany. [email protected].
PMID: 39707025 DOI: 10.1038/s44318-024-00331-x
Abstract

The cytosolic nucleic acid sensors RIG-I and cGAS induce type-I interferon (IFN)-mediated immune responses to RNA and DNA viruses, respectively. So far no connection between the two cytosolic pathways upstream of IKK-like kinase activation has been investigated. Here, we identify heterogeneous nuclear ribonucleoprotein M (hnRNPM) as a positive regulator of IRF3 phosphorylation and type-I IFN induction downstream of both cGAS and RIG-I. Combining interactome analysis with genome editing, we further uncover the RNA-binding protein ELAV-like protein 1 (ELAVL1; also known as human antigen R, HuR) as an hnRNPM interactor. Depletion of hnRNPM or ELAVL1 impairs type-I IFN induction by herpes simplex virus 1 or Sendai virus. In addition, we show that hnRNPM and ELAVL1 interact with TANK-binding kinase 1, IκB kinase ε, IκB kinase β, and NF-κB p65. Our confocal microscopy experiments demonstrate cytosolic and perinuclear interactions between hnRNPM, ELAVL1, and TBK1. Furthermore, pharmacological inhibition of ELAVL1 strongly reduces cytokine release from type-I interferonopathy patient fibroblasts. The RNA-binding proteins hnRNPM and ELAVL1 are the first non-redundant regulators to bridge the cGAS/STING and RIG-I/MAVS pathways. Overall, our study characterizes the hnRNPM-ELAVL1 complex as a novel system promoting Antiviral defense, pointing to a potential therapeutic target to reduce auto-inflammation in patients with type-I interferonopathies.

Keywords
ELAVL1; IRF3; RIG-I Signaling; cGAS Signaling; hnRNPM.
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