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

ABSTRACT: RIG-I like helicases (RLHs) and cGAS are crucial cytosolic sensors of viral RNA and DNA, respectively, and induce type I IFNs via TBK1/IKKε. hnRNPM was described to possess antimicrobial activities. Here, we show that hnRNPM promotes IRF3 phosphorylation and type I IFN induction downstream of cGAS and RIG-I in THP-1 cells and primary human fibroblasts. Interactome analysis revealed that hnRNPM forms a multiprotein complex with ELAVL1, TBK1, IKKε, IKKβ, and NF-κB p65. hnRNPM, ELAVL1, and TBK1 predominantly interacted in the cytosol. To our knowledge, hnRNPM and ELAVL1 represent the first non-redundant signaling components merging the cGAS-STING and RIG-I–MAVS pathways. Therefore, our findings may have implications for host defense and auto-inflammatory diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184273 | GEO | 2023/09/16

REPOSITORIES: GEO

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hnRNPM, ELAVL1, and TBK1 form a type I interferon-inducing multiprotein complex downstream of cGAS and RIG-I

Project description:RIG-I like helicases (RLHs) and cGAS are crucial cytosolic sensors of viral RNA and DNA, respectively, and induce type I IFNs via TBK1/ IKKe. hnRNPM was described to possess antimicrobial activities. Here, we show that hnRNPM promotes TBK1/IRF3 phosphorylation and type I IFN induction downstream of cGAS and RIG-I in THP-1 cells and primary human fibroblasts. Interactome analysis revealed that hnRNPM forms a multiprotein complex with ELAVL1, SON, TBK1, IKKe, IKKb, and NFkB p65. The purified hnRNPM complex enhanced TBK1 phosphorylation. Vice versa, TBK1 directly phosphorylated ELAVL1. hnRNPM, ELAVL1, and TBK1 predominantly interacted in the cytosol close to the nuclear membrane. Of note, patients with mutations in SON suffer from recurrent infections, underlining its biologic significance. To our knowledge, hnRNPM, ELAVL1, and SON represent the first non-redundant signaling components merging the cGAS-STING and RIG-I–MAVS pathways. Therefore, our findings may have implications for host defense and auto-inflammatory diseases.

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