Abstract

Antiviral innate immune response to RNA virus infection is supported by Pattern-Recognition Receptors (PRR) including RIG-I-Like Receptors (RLR), which lead to type I interferons (IFNs) and IFN-stimulated genes (ISG) production. Upon sensing of viral RNA, the E3 ubiquitin ligase TNF Receptor-Associated Factor-3 (TRAF3) is recruited along with its substrate TANK-Binding Kinase (TBK1), to MAVS-containing subcellular compartments, including mitochondria, peroxisomes, and the mitochondria-associated endoplasmic reticulum membrane (MAM). However, the regulation of such events remains largely unresolved. Here, we identify TRK-Fused Gene (TFG), a protein involved in the transport of newly synthesized proteins to the endomembrane system via the Coat Protein complex II (COPII) transport vesicles, as a new TRAF3-interacting protein allowing the efficient recruitment of TRAF3 to MAVS and TBK1 following Sendai virus (SeV) infection. Using siRNA and shRNA approaches, we show that TFG is required for virus-induced TBK1 activation resulting in C-terminal IRF3 phosphorylation and dimerization. We further show that the ability of the TRAF3-TFG complex to engage mTOR following SeV infection allows TBK1 to phosphorylate mTOR on serine 2159, a post-translational modification shown to promote mTORC1 signaling. We demonstrate that the activation of mTORC1 signaling during SeV infection plays a positive role in the expression of Viperin, IRF7 and IFN-induced proteins with tetratricopeptide repeats (IFITs) proteins, and that depleting TFG resulted in a compromised antiviral state. Our study, therefore, identifies TFG as an essential component of the RLR-dependent type I IFN antiviral response.

Highlights

  • The cellular antiviral innate immune response against invading pathogens represents a critical step in maintaining cell homeostasis and host survival

  • TRK-Fused Gene (TFG) seems to accumulate in a perinuclear region (Fig 1D) where it can interact with TNF Receptor-Associated Factor-3 (TRAF3)

  • Our group previously observed that TRAF3 mainly colocalizes with markers of the ER-Exit-Sites (ERES), ER-to-Golgi intermediate compartment (ERGIC) and the cisGolgi apparatus [48]

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Summary

Introduction

The cellular antiviral innate immune response against invading pathogens represents a critical step in maintaining cell homeostasis and host survival. These receptors include the endosome localized Tolllike receptors (TLRs) TLR3, TLR7, TLR8, TLR9, the cytosolic cyclic GMP-AMP synthase (cGAS) as well as retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), RIG-I, and melanoma differentiation-associated gene 5 (MDA5) [5,6,7,8] Even if these TLRs are involved in the detection of extracellular viral nucleic acids of key immune cells, most other cell types, such as epithelial cells and fibroblasts, rely mainly on cytosolic RLRs to sense RNA replication intermediates [9,10,11]

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