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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Alexander Kirchhoff - , University of Bonn Medical Center (Author)
  • Anna-Maria Herzner - , Boehringer Ingelheim GmbH (Author)
  • Christian Urban - , Technical University of Munich (Author)
  • Antonio Piras - , Technical University of Munich (Author)
  • Robert Düster - , University of Bonn Medical Center (Author)
  • Julia Mahlberg - , University of Bonn Medical Center (Author)
  • Agathe Grünewald - , University of Bonn Medical Center (Author)
  • Thais M Schlee-Guimarães - , University of Bonn Medical Center (Author)
  • Katrin Ciupka - , University of Bonn Medical Center (Author)
  • Petro Leka - , University of Bonn Medical Center (Author)
  • Robert J Bootz - , University of Bonn Medical Center (Author)
  • Christina Wallerath - , University of Bonn Medical Center (Author)
  • Charlotte Hunkler - , University of Bonn Medical Center (Author)
  • Ann Kristin de Regt - , University of Bonn Medical Center (Author)
  • Beate M Kümmerer - , German Center for Infection Research, Partner Site Bonn-Cologne (Author)
  • Maria Hønholt Christensen - , University of Bonn Medical Center (Author)
  • Florian I Schmidt - , University of Bonn Medical Center (Author)
  • Min Ae Lee-Kirsch - , Department of Paediatrics, University Hospital Carl Gustav Carus Dresden, German Center for Child and Adolescent Health (DZKJ) - Partner Site Leipzig/Dresden (Author)
  • Claudia Günther - , Department of Dermatology, Medical Faculty Carl Gustav Carus (Author)
  • Hiroki Kato - , University of Bonn Medical Center (Author)
  • Eva Bartok - , University of Bonn Medical Center (Author)
  • Gunther Hartmann - , University of Bonn Medical Center (Author)
  • Matthias Geyer - , University of Bonn Medical Center (Author)
  • Andreas Pichlmair - , German Center for Infection Research, Partner Site Munich (Author)
  • Martin Schlee - , University of Bonn Medical Center (Author)

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.

Details

Original languageEnglish
Article number107492
JournalThe EMBO journal
Publication statusE-pub ahead of print - 20 Dec 2024
Peer-reviewedYes

External IDs

Scopus 85212865879
ORCID /0000-0002-4330-1861/work/176344086