RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination

Nila Roy Choudhury; Gregory Heikel; Maryia Trubitsyna; Peter Kubik; Jakub Stanislaw Nowak; Shaun Webb; Sander Granneman; Christos Spanos; Juri Rappsilber; Alfredo Castello; Gracjan Michlewski

The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. . https://doi.org/10.1101/200410 doi: bioRxiv preprint mediated dimerization of the transcription factor IRF3, leading to type I interferon (interferon α and β ) expression (Loo and Gale, 2011; Yoneyama et al., 2004) . K63-linked ubiquitination of RIG-I by TRIM25 is required for an efficient interferon response (Gack et al., 2007) . RIG-I can also be stimulated by unanchored polyubiquitin chains generated by TRIM25 (Zeng et al., 2010) . This interaction is targeted by viruses to suppress the interferon response. For example, the influenza's RNA-binding protein NS1 inhibits TRIM25-mediated ubiquitination of RIG-I by binding to the TRIM25 CC domain and disrupting its dimerization, allowing the virus to avoid the innate immune response (Gack et al., 2009) . This inhibitory activity is significantly reduced in an NS1 mutant R38A/K41A, which cannot bind RNA (Donelan et al., 2003) . This raises questions about a possible functional link between the RNA-binding activities of TRIM25 and NS1. Finally, SARS-CoV nucleocapsid protein (N-protein) has been shown to inhibit TRIM25 by binding to TRIM25's PRY/SPRY domain (Hu et al., 2017) .