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

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.

The Kinase MAP4K1 Inhibits Cytosolic RNA-Induced Antiviral Signaling by Promoting Proteasomal Degradation of TBK1/IKKε

“…It has been reported that TBK1 activity can be regulated by kinase activity modulation, posttranslational modification such as phosphorylation or ubiquitination, as well as prevention of functional TBK1-containing complex formation ( 37 , 38 ). It was reported that NLRP4-DTX4, TRIP Siglec1-TRIM27, THOC7, and TRAF3IP3 promote K48-linked polyubiquitination of TBK1 ( 19 , 34 , 39 , 40 ). Although many inhibitors were found or patented, there is still much to be understood by searching more interaction partners of TBK1.…”

Regulation of antiviral innate immune signaling and viral evasion following viral genome sensing

“… Signaling molecule Classification Regulator Function Ref. TBK1 PTMs Positive MIB K63-linked ubiquitination 161 TBK1 K63-linked ubiquitination 154 Nrdp1 K63-linked ubiquitination 163 RNF128 K63-linked ubiquitination 162 USP1–UAF1 complex Deubiquitination 164 UBQLN2 Phosphorylation 159 Src Autophosphorylation 160 TBK1 Autophosphorylation 155 RKIP Autophosphorylation 158 GSK3β Self-association and autophosphorylation 157 Dnmt3a Recruitment of HDAC9 for deacetylation 165 HDAC3 Deacetylation 166 TRIM9 Recruitment of GSK3β for activation 157 Negative ASB8 K48-linked ubiquitination 172 USP38 K48-linked ubiquitination 176 DYRK2 K48-linked ubiquitination 174 THOC7 K48-linked ubiquitination 175 TRIP K48-linked ubiquitination 173 Siglec1 Recru...…”

“…In contrast, several TBK1-regulating proteins negatively impact TBK1. K48-linked polyubiquitination of TBK1 induced by E3 ubiquitin ligases such as SOCS box-containing 8 (ASB8) 172 , TRAF-interacting protein 173 , dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) 174 , and THO complex subunit 7 homolog (THOC7) 175 triggers proteasomal degradation of TBK1 and ultimately terminates immune activation. Interestingly, USP38 permits K48-linked ubiquitination and subsequent degradation of TBK1 by specifically removing K33-linked ubiquitin chains from the same lysine site on TBK1 176 .…”

Protein Synthesis by Day 16 Bovine Conceptuses during the Time of Maternal Recognition of Pregnancy

“…We did identify a number of other proteins with heavy labelled peptides in CCM from three or more conceptuses, with light labelled versions of these proteins also identified in the CCM from other conceptuses ( Table 3) included THO complex subunit 7 homolog, THOC7. Interestingly, THOC7 has been suggested to negatively regulate type I IFN production [50]. Another protein present in the media from five conceptuses (heavy labelled in CCM from three conceptuses) is GPRC5A.…”