Recently, Professor Jia Renyong's group at the Institute of Veterinary Medicine and Immunology published two consecutive papers in the Journal of Virology entitled "Duck Tembusu Virus Inhibits Type I Interferon Production through the JOSD1-SOCS1-IRF7 Negative-Feedback Regulation Pathway" (link to paper https://doi.org/10.1128/jvi.00930-22) and "RNF123 mediates ubiquination of SOCS1 to regulate type I interferon production during Duck Tembusu Virus infection" (link to paper https://doi.org/10.1128/jvi.00930-22). ) and "RNF123 mediates ubiquitination and degradation of SOCS1 to regulate type I interferon production during Duck Tembusu Virus infection" (link to paper https://doi.org/10.1128/jvi.00095-23), the first research paper reported the latest research findings on the regulation of type I interferon (IFN) signalling by the SOCS1 protein in Duck Tembusu Virus (DTMUV), which provides an important theoretical basis for effective prevention and control of the disease.
DTMUV belongs to the genus Flavivirus of the family Flaviviridae, which primarily causes immune organ damage, neurological dysfunction and reduced egg production in waterfowl, often resulting in severe economic losses to the waterfowl industry. Pre-infection with DTMUV was found to render the virus unaffected by late IFN treatment, but the pathway by which DTMUV inhibits the antiviral effect of type I IFN is unclear, and the reason for the up-regulation of SOCS1 during DTMUV infection has not been elucidated.
The group showed that activation of the TLR3 pathway promotes SOCS1 expression during DTMUV infection, and that upregulated SOCS1 promotes DTMUV replication by mediating K48-linked ubiquitination and proteasomal degradation of IRF7, thereby antagonising type I IFN signalling. Further studies revealed that the SOCS1 protein itself is modified by K48-linked ubiquitination, that JOSD1 acts as a deubiquitinating enzyme to mediate SOCS1 deubiquitination and thereby stabilise SOCS1 expression, and that JOSD1 inhibits type I IFN production during DTMUV infection by stabilising SOCS1 expression.
Although the mechanism of SOCS1 up-regulation during DTMUV infection was elucidated, it was confirmed which E3 ubiquitin ligase mediates the ubiquitination of SOCS1. K48-linked ubiquitination and proteasomal degradation of SOCS1 ultimately promoted TLR3/IRF7-induced type I IFN expression and suppressed viral replication.
This study systematically revealed a new mechanism of viral regulation of type I IFN signalling by SOCS1 protein during DTMUV infection, and for the first time demonstrated that the E3 ubiquitin ligase RNF123 mediates the K48-linked ubiquitination of SOCS1, which also provides an important theoretical basis for elucidating whether other flaviviruses use SOCS1 protein to inhibit the type I IFN signalling mechanism.
Shanzhi Huang, a 2020 PhD student in preventive veterinary medicine at the Institute of Veterinary Medicine and Immunology, was the first author, and Prof Anchun Cheng and Prof Renyong Jia were co-corresponding authors. This study was supported by the National Natural Science Foundation of China (32172833) and the Natural Science Foundation of Sichuan Province (2022NSFSC0078).
