ZFIN ID: ZDB-PUB-201027-9
A Novel Transcript Isoform of TBK1 Negatively Regulates Type I IFN Production by Promoting Proteasomal Degradation of TBK1 and Lysosomal Degradation of IRF3
Zhang, J., Wu, X.M., Hu, Y.W., Chang, M.X.
Date: 2020
Source: Frontiers in immunology   11: 580864 (Journal)
Registered Authors:
Keywords: IRF3, TBK1, TBK1 isoform, protein degradation, ubiquitination
MeSH Terms:
  • Animals
  • Cells, Cultured
  • Fish Proteins/genetics
  • Fish Proteins/metabolism*
  • HEK293 Cells
  • Humans
  • Interferon Regulatory Factor-3/metabolism*
  • Interferon Type I/metabolism
  • Lysosomes/metabolism*
  • Proteasome Endopeptidase Complex/metabolism*
  • Protein Isoforms/genetics
  • Protein Isoforms/metabolism*
  • Protein-Serine-Threonine Kinases/genetics
  • Protein-Serine-Threonine Kinases/metabolism*
  • Proteolysis
  • Signal Transduction
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 33101307 Full text @ Front Immunol
ABSTRACT
TANK-binding kinase 1 (TBK1), an IKK-related serine/threonine kinase, is pivotal for the induction of antiviral type I interferon (IFN) by TLR and RLR signaling pathways. In a previous study, we demonstrated that TBK1 spliced isoforms (TBK1_tv1 and TBK1_tv2) from zebrafish were dominant negative regulators in the RLR antiviral pathway by targeting the functional TBK1-IRF3 complex formation. In this study, we show that the third TBK1 isoform (namely TBK1_tv3) inhibits zebrafish type I IFN production by promoting TBK1 and IRF3 degradation. First, ectopic expression of TBK1_tv3 suppresses poly(I:C)- and Spring viremia of carp virus-induced type I IFN response, and also inhibits the up-regulation of IFN promoter activities stimulated by RIG-I, MDA5, MAVS, TBK1, and IRF3. Second, TBK1_tv3 targets TBK1 and IRF3 to impair the formation of TBK1 dimer, TBK1-IRF3 complex, and IRF3 dimer. Notably, TBK1_tv3 promotes the degradation of TBK1 through the ubiquitin-proteasome pathway and the degradation of IRF3 through the lysosomal pathway. Further analysis demonstrates that TBK1_tv3 promotes the degradation of TBK1 for K48-linked ubiquitination by targeting the K251, K256, and K271 sites of TBK1. Collectively, our results suggest a novel TBK1 isoform-mediated negative regulation mechanism, which serves to balance the production of type I IFN and ISGs.
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