Towards understanding the link between TRIM25’s RNA binding and antiviral activity

• Applicants: Professor Dr. Janosch Hennig; Julia Mahamid, Ph.D.
• Subject Area: Biochemistry ; Biophysics ; Immunology ; Structural Biology ; Virology ; Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 553843738

Viruses pose a great risk to humanity as proven by recent epidemic outbreaks. Therefore, we need a deeper understanding of the molecular mechanism of the innate immune response against viral infections. Often, the ubiquitin system plays an important role in triggering the antiviral defense mechanism of the host. Of special importance are here E3 ligases, which mediate the transfer of ubiquitin to their substrate, thereby initiating an antiviral response. The tripartite motif (TRIM) protein family of E3 ligases has often been shown to be involved in activating pattern recognition receptors. TRIM25 has been shown to ubiquitinate RIG-I, which activates antiviral signaling pathways, leading to production of interferons and pro-inflammatory cytokines. TRIM25 also binds RNA and we could provide insights into its RNA binding mechanism. Further, we could show that RNA binding is essential for TRIM25’s antiviral activity and that a biomolecular condensation mechanism localizes TRIM25 to viral factories within the host cell. In the proposed research, we want to decipher the molecular grammar of TRIM25’s antiviral activity and its dependence on RNA binding and condensation by combining biophysical experiments, NMR and cryo-ET with cellular data including infection scenarios with a different range of RNA viruses. This work could provide the means to develop a therapeutic strategy with TRIM25 at its center against RNA viruses.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Mikhail Savitski, Ph.D.