Unknown

Dataset Information

0

A Novel Transcript Isoform of TBK1 Negatively Regulates Type I IFN Production by Promoting Proteasomal Degradation of TBK1 and Lysosomal Degradation of IRF3.


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.

SUBMITTER: Zhang J 

PROVIDER: S-EPMC7554342 | BioStudies | 2020-01-01

REPOSITORIES: biostudies

Similar Datasets

2019-01-01 | S-EPMC6410154 | BioStudies
2018-01-01 | S-EPMC5797597 | BioStudies
1000-01-01 | S-EPMC3372421 | BioStudies
2020-01-01 | S-EPMC7354440 | BioStudies
2018-01-01 | S-EPMC6146813 | BioStudies
2015-01-01 | S-EPMC4583546 | BioStudies
2012-01-01 | S-EPMC3549669 | BioStudies
2012-01-01 | S-EPMC3760161 | BioStudies
2011-01-01 | S-EPMC3041802 | BioStudies
2018-01-01 | S-EPMC5897779 | BioStudies