Key Points
Zebrafish fbxo3 negatively regulates antiviral responses.
Zebrafish fbxo3 inhibits expression of antiviral response genes upon SVCV infection.
Zebrafish fbxo3 promotes degradation of irf3 and irf7 by catalyzing ubiquitination.
Abstract
FBXO3, belongs to the F-box family of proteins, which has been reported to involve in host autoimmune and inflammatory responses by promoting its substrates for ubiquitylation. However, thus far, its physiological function in antiviral immunity remains elusive. In this study, we report that overexpression of zebrafish fbxo3 suppresses cellular antiviral responses. Moreover, disruption of fbxo3 in zebrafish increases the survival rate upon spring viremia of carp virus exposure. Further assays indicate that fbxo3 interacts with irf3/irf7 and specifically catalyzes K27-linked ubiquitination of irf3 and irf7, resulting in proteasomal degradation of irf3 and irf7. However, the F-box domain of fbxo3 is not required for fbxo3 to interact with irf3/irf7 and to inhibit transactivity of irf3 and irf7. This study provides novel insights into fbxo3 function and the underlying mechanisms. In addition, it sheds new light on the regulation of IFN-I signaling by F-box proteins.
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Footnotes
This work was supported by Strategic Priority Research Program of the Chinese Academy of Sciences Grant XDA24010308, National Natural Science Foundation of China Grants 31830101, 31721005, and 31671315, and National Key Research and Development Program of China Grant 2018YFD0900602.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- CHX
- cycloheximide
- CPE
- cytopathic effect
- dpf
- day postfertilization
- EPC
- epithelioma papulosum cyprini
- HEK
- human embryonic kidney
- IFN-I
- type I IFN signaling
- IRF
- IFN regulatory factor
- ISRE
- IFN-stimulated response element
- M1
- mutant 1
- M2
- mutant 2
- MAVS
- mitochondrial antiviral signaling protein
- MOI
- multiplicity of infection
- mpf
- month postfertilization
- PTM
- posttranslational modification
- qRT-PCR
- quantitative real-time PCR
- RIG-I
- retinoic acid–inducible gene-I
- RLR
- RIG-I–like receptor
- SCF
- SKP1–Cullin1–F-box
- sgRNA
- single-guide RNA
- SVSC
- spring viremia of carp virus
- TCID50
- 50% tissue culture–infective dose
- WT
- wild-type
- ZFL
- zebrafish liver.
- Received March 20, 2020.
- Accepted July 29, 2020.
- Copyright © 2020 by The American Association of Immunologists, Inc.
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