Research
| Title： | Zebrafish CERKL Enhances Host TBK1 Stability and Simultaneously Degrades Viral Protein via Ubiquitination Modulation |
|---|---|
| First author： | Chen, Dan-Dan; Lu, Long-Feng; Xiong, Feng; Wang, Xue-Li; Jiang, Jing-Yu; Zhang, Can; Li, Zhuo-Cong; Han, Ke-Jia; Li, Shun |
| Journal： | JOURNAL OF IMMUNOLOGY |
| Years： | 2022 |
| DOI： | 10.4049/jimmunol.2101007 |
| Abstract： | 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, ifnu1 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. The Journal of Immunology, 2022,208: 2196-2206. |
