biostudies-literatureKirchhoff ADeutsche Forschungsgemeinschaft (DFG)Ministry of Education and Research (BMBF)824-853https://www.ebi.ac.uk/biostudies/studies/S-EPMC11791083biostudies-literatureUnknown44(3)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 kiThe EMBO journalRNA-binding proteins hnRNPM and ELAVL1 promote type-I interferon induction downstream of the nucleic acid sensors cGAS and RIG-I.PMC11791083Bo&MeRanG GRK 2168CRC237 369799452/A1117479373501GL2405HSCHL1930/1-2322568668CRC237 369799452/B2101GM2206C216372545388159768EXC2151 - 390873048GRK2168 272482170CRC369 501752319/C06TRR259 397484323SFB670TRR237 - 369799452Lee-Kirsch MACiupka KMahlberg JGunther CBartok EKato HKummerer BMWallerath CSchmidt FIBootz RJChristensen MHUrban CGeyer MSchlee-Guimaraes TMHunkler CPiras ASchlee Mde Regt AKHerzner AMDuster RLeka PHartmann GKirchhoff AGrunewald APichlmair AfalseRNA-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 ki2025-01-01T00:00:00Z2025 Feb2025-04-04T00:54:54.081Z2025-04-04T00:54:54.081ZS-EPMC117910833970702510.1038/s44318-024-00331-x