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

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

Affiliations

  • 1 Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany. alkirchhoff@web.de.
  • 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. martin.schlee@uni-bonn.de.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100685
    99.45%, MLCK Inhibitor