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

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.