Ebola Virus VP35 Interacts Non-Covalently with Ubiquitin Chains to Promote Viral Replication Creating New Therapeutic Opportunities

 Ebolavirus (EBOV) causes severe hemorrhagic fever in humans, relying on the viral polymerase complex with VP35 as a crucial factor. VP35 undergoes covalent ubiquitination, fundamental for regulating its interaction within the complex, aiding virus replication. VP35 also participates in non-covalent interaction with ubiquitin (Ub), the purpose of which was unclear. This research unveils VP35's specific interaction with free K63-linked polyUb chains. Manipulating Isopeptidase T (USP5), responsible for degrading unanchored polyUb chains, reduced VP35's association with Ub. This decrease correlated with diminished polymerase activity, impacting EBOV replication. Through computational modeling, the authors mapped the VP35-Ub non-covalent interaction, validated the interface with mutations, and identified compounds disrupting this interaction. These compounds effectively reduced viral polymerase activity, impeding infectious EBOV replication. This study sheds light on the role of unanchored polyUb chains in regulating Ebola virus polymerase function. Additionally, the discovery of compounds disrupting VP35-Ub interactions holds promise for potential anti-Ebola virus therapies.

(LA)