Smyd3 negatively regulates the anti-viral pathway by promoting TAK1 degradation in teleost fish

Abstract

ABSTRACT Transforming growth factor beta kinase 1 (TAK1, also known as MAP3K7) has been identified as an adaptor protein in the NF-κB and IRF3 signaling pathways in teleost fishes, and it plays a crucial role in both inflammatory responses and anti-viral actions. SET and MYND domain protein 3 (Smyd3) belongs to the Smyd3 lysine methylase family and possess significant functions in the methylation process of diverse histone and non-histone targets. However, the exact role of Smyd3 in innate immune regulation has not yet been fully elucidated. Siniperca chuatsi rhabdovirus (SCRV) is a negative single-stranded RNA virus that has the potential to cause widespread fish diseases. In this study, we discovered that overexpression of Smyd3 facilitates the replication of SCRV, enabling the virus to evade detection of the immune system through Smyd3. Furthermore, we observed that Smyd3 promotes the degradation of TAK1 by inducing K48-linked ubiquitination of TAK1. As a result, Smyd3 exerts a negative regulatory effect on the TAK1-mediated NF-κB signaling pathway and the IRF3 signaling pathway. Thus, our findings demonstrate that Smyd3 plays a role in promoting the degradation of the TAK1 protein. Moreover, we discovered that the degradation of TAK1 by Smyd3 occurs independently of its methyltransferase activity. This study not only enhances our understanding of anti-viral immunity in fish but also offers a novel perspective for investigating anti-viral immunity in mammals. IMPORTANCE In this study, we have found that the existence of Smyd3 promoted the replication of SCRV. Additionally, we report that Smyd3 negatively regulates the NF-κB and IRF3 signaling pathway by facilitating the degradation of TAK1 in fish. Our findings suggest that Smyd3 interacts with TAK1. Further investigations have revealed that Smyd3 specifically mediates K48-linked ubiquitination of TAK1 and enhances TAK1 degradation, resulting in a significant inhibition of the NF-κB and IRF3 signaling pathway. These results not only contribute to the advancement of fish anti-viral immunity but also provide new evidence for understanding the mechanism of TAK1 in mammals.