THO Complex Subunit 7 Homolog Negatively Regulates Cellular Antiviral Response against RNA Viruses by Targeting TBK1.

Tian-Sheng He,Weiying Wang,Lingzhen Cao,Cynthia Ju,Ya-Xian Yang,Hua Rao,Jing Li,Changsheng Li,Tao Xie,Liang-Guo Xu

doi:10.3390/v11020158

Tian-Sheng He, Weiying Wang + Show 8 more

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https://doi.org/10.3390/v11020158

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Abstract

RNA virus invasion induces a cytosolic RIG-I-like receptor (RLR) signaling pathway by promoting assembly of the Mitochondrial antiviral-signaling protein (MAVS) signalosome and triggers the rapid production of type I interferons (IFNs) and proinflammatory cytokines. During this process, the pivotal kinase TANK binding kinase 1 (TBK1) is recruited to the MAVS signalosome to transduce a robust innate antiviral immune response by phosphorylating transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor (NF)-κB and promoting their nuclear translocation. However, the molecular mechanisms underlying the negative regulation of TBK1 are largely unknown. In the present study, we found that THO complex subunit 7 homolog (THOC7) negatively regulated the cellular antiviral response by promoting the proteasomal degradation of TBK1. THOC7 overexpression potently inhibited Sendai virus- or polyI:C-induced IRF3 dimerization and phosphorylation and IFN-β production. In contrast, THOC7 knockdown had the opposite effects. Moreover, we simulated a node-activated pathway to show that THOC7 regulated the RIG-I-like receptors (RLR)-/MAVS-dependent signaling cascade at the TBK1 level. Furthermore, THOC7 was involved in the MAVS signalosome and promoted TBK1 degradation by increasing its K48 ubiquitin-associated polyubiquitination. Together, these findings suggest that THOC7 negatively regulates type I IFN production by promoting TBK1 proteasomal degradation, thus improving our understanding of innate antiviral immune responses.

Highlights

Cellular innate immune responses are initiated by the detection of “non-self” conserved molecular motifs of invading microbial pathogens, such as pathogen-associated molecular patterns [1], or “self”tissue damage-inducing molecules released by host necrotic cells, such as danger-associated molecular patterns [2]
The yeast two-hybrid screening assay identified THO complex subunit 7 homolog (THOC7) (GenBank accession number: NM_025075.3) as a candidate protein that interacted with TANK binding kinase 1 (TBK1), which was confirmed by gene sequencing and BLAST analysis
Interferon-stimulated gene ISG56 mRNA induced by viruses. These results indicate that THOC7 negatively regulates the innate immune response against RNA viruses

Summary

Introduction

Tissue damage-inducing molecules released by host necrotic cells, such as danger-associated molecular patterns [2]. Viruses 2019, 11, 158 activation and recruitment domain (CARD)–CARD interactions through the CARD domains of RIG-I and a central antiviral adaptor protein known as MAVS, which is referred to as VISA, IPS-1, and Cardif [7,8,9,10] and located in the mitochondria. The MAVS signalosome recruits the important kinase TBK1 to activate the transcription factors IRF3 and NF-κB, followed by their nuclear translocation and high production of type I interferons (IFNs) and proinflammatory cytokines [12]. TBK1, a member of a noncanonical IKK family of serine/threonine kinases, is ubiquitously expressed in various cells and acts as a key node protein for regulating IRF3 activity and downstream type I IFN production [13]. TBK1 is suggested to phosphorylate three vital adaptor proteins, MAVS, Stimulator of interferon genes protein (STING), and TIR domain-containing adapter protein inducing

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