RNA-binding proteins hnRNPM and ELAVL1 promote type-I interferon induction downstream of the nucleic acid sensors cGAS and RIG-I
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.
Authors
- Katrin Ciupka (ORCID: https://orcid.org/0000-0002-8283-7597)
- Anna‐Maria Herzner (ORCID: https://orcid.org/0000-0001-6746-0587)
- Maria H. Christensen (ORCID: https://orcid.org/0000-0003-4778-3009)
- Thais Marina Schlee-Guimaraes (ORCID: https://orcid.org/0000-0002-3710-6322)
- Agathe Grünewald
- Christina Wallerath (ORCID: https://orcid.org/0000-0002-8095-6111)
- Hiroki Kato (ORCID: https://orcid.org/0000-0002-9571-4895)
- Alexander Kirchhoff (ORCID: https://orcid.org/0000-0002-8796-1829)
- Julia Mahlberg (ORCID: https://orcid.org/0000-0001-8103-8040)
- Robert Düster (ORCID: https://orcid.org/0000-0003-4954-6883)
- Claudia Günther (ORCID: https://orcid.org/0000-0002-4330-1861)
- Florian Ingo Schmidt (ORCID: https://orcid.org/0000-0002-9979-9769)
- Christian Urban (ORCID: https://orcid.org/0000-0002-4080-2468)
- Beate Mareike Kümmerer (ORCID: https://orcid.org/0000-0002-9011-2764)
- Eva Bartok (ORCID: https://orcid.org/0000-0003-0556-1950)
- Andreas Pichlmair (ORCID: https://orcid.org/0000-0002-0166-1367)
- Matthias Geyer (ORCID: https://orcid.org/0000-0002-7718-5002)
- Ann Kristin de Regt
- Gunther Hartmann (ORCID: https://orcid.org/0000-0003-1021-2018)
- Antonio Piras (ORCID: https://orcid.org/0000-0002-5724-9355)
- Charlotte Hunkler
- Martin Schlee (ORCID: https://orcid.org/0000-0003-3671-7639)
- Petro Leka
- Robert J. Bootz (ORCID: https://orcid.org/0000-0002-3889-958X)
- Min Ae Lee-Kirsch
Institutions
- Boehringer Ingelheim (Germany) (DE)
- University Hospital Bonn (DE)
- German Center for Infection Research (DE)
- University Hospital Carl Gustav Carus (DE)
- Technical University of Munich (DE)
- Instituut voor Tropische Geneeskunde (BE)
- Technische Universität Dresden (DE)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-12-20
- DOI
- https://doi.org/10.1038/s44318-024-00331-x
- Citations
- 5
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 1.20
Funders
- Deutsche Forschungsgemeinschaft