TRIM38 Inhibits Zika Virus by Upregulating RIG-I/MDA5 Pathway and Promoting Ubiquitin-Mediated Degradation of Viral NS3 Protein

Members of the tripartite motif (TRIM)-containing protein family play crucial roles in regulating immune system responses. The TRIM38 protein regulates host innate immunity and directly degrades some viral proteins through its E3 ubiquitin ligase activity. This study demonstrated that Zika virus (ZIKV) infection can promote the expression of TRIM38 in human glioma cells (U251). TRIM38 overexpression restricted ZIKV replication in U251 cells, while TRIM38 knockout enhanced ZIKV replication. TRIM38 overexpression upregulated the RIG-I/MDA5 pathway and promoted the level of IFN-beta early during viral infection, while TRIM38 knockout had the opposite effect. In addition, TRIM38 interacts with ZIKV non-structural protein 3 (NS3) and degrades the NS3 protein through a lysosome-dependent manner via the E3 ligase activity of TRIM38. Deletion of the RING domain of TRIM38 abrogates its interaction with NS3 and impairs the antiviral activity of TRIM38. Our results indicate that TRIM38 is a novel antiviral protein against ZIKV, and it exerts antiviral activity by upregulating the RIG-I/MDA5 pathway, increasing IFN-beta levels, and degrading the viral NS3 protein.