Zebrafish CERKL Enhances Host TBK1 Stability and Simultaneously Degrades Viral Protein via Ubiquitination Modulation
- Chen, D.D., Lu, L.F., Xiong, F., Wang, X.L., Jiang, J.Y., Zhang, C., Li, Z.C., Han, K.J., Li, S.
- Journal of immunology (Baltimore, Md. : 1950) 208(9): 2196-2206 (Journal)
- Registered Authors
- Xiong, Feng
- MeSH Terms
- DNA Viruses
- Fish Diseases*
- Phosphotransferases (Alcohol Group Acceptor)
- Rhabdoviridae Infections*
- Viral Proteins
- Zebrafish Proteins/chemistry
- Zebrafish Proteins/metabolism
- 35418468 Full text @ J. Immunol.
Chen, D.D., Lu, L.F., Xiong, F., Wang, X.L., Jiang, J.Y., Zhang, C., Li, Z.C., Han, K.J., Li, S. (2022) Zebrafish CERKL Enhances Host TBK1 Stability and Simultaneously Degrades Viral Protein via Ubiquitination Modulation. Journal of immunology (Baltimore, Md. : 1950). 208(9):2196-2206.
In the viral infection process, host gene function is usually reported as either defending the host or assaulting the virus. In this study, we demonstrated that zebrafish ceramide kinase-like (CERKL) mediates protection against viral infection via two distinct mechanisms: stabilization of TANK-binding kinase 1 (TBK1) through impairing K48-linked ubiquitination and degradation of spring viremia of carp virus (SVCV) P protein by dampening K63-linked ubiquitination, resulting in an improvement of the host immune response and a decline in viral activity in epithelioma papulosum cyprini (EPC) cells. On SVCV infection, ifnφ1 expression was increased or blunted by CERKL overexpression or knockdown, respectively. Subsequently, we found that CERKL localized in the cytoplasm, where it interacted with TBK1 and enhanced its stability by impeding the K48-linked polyubiquitination; meanwhile, the antiviral capacity of TBK1 was significantly potentiated by CERKL. In contrast, CERKL also interacted with and degraded SVCV P protein to disrupt its function in viral proliferation. Further mechanism analysis revealed K63-linked deubiquitination is the primary means of CERKL-mediated SVCV P protein degradation. Taken together, our study reveals a novel mechanism of fish defense against viral infection: the single gene cerkl is both a shield for the host and a spear against the virus, which strengthens resistance.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes