Ebola virus VP35 interacts non-covalently with ubiquitin chains to promote viral replication

Carlos Rodriguez Salazar, Sarah van Tol, Olivier Mailhot, Maria Gonzalez-Orozco, Gabriel T. Galdino, Abbey N. Warren, Natalia Teruel, Padmanava Behera, Kazi Sabrina Afreen, Lihong Zhang, Terry L. Juelich, Jennifer K. Smith, María Inés Zylber, Alexander N. Freiberg, Rafael J. Najmanovich, Maria I. Giraldo, Ricardo Rajsbaum Gorodezky

Research output: Contribution to journalArticlepeer-review

Abstract

AU Ebolavirus: Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly (EBOV) belongs to a family of highly pathogenic :viruses that cause severe hemorrhagic fever in humans. EBOV replication requires the activity of the viral polymerase complex, which includes the cofactor and Interferon antagonist VP35. We previously showed that the covalent ubiquitination of VP35 promotes virus replication by regulating interactions with the polymerase complex. In addition, VP35 can also interact non-covalently with ubiquitin (Ub); however, the function of this interaction is unknown. Here, we report that VP35 interacts with free (unanchored) K63-linked polyUb chains. Ectopic expression of Isopeptidase T (USP5), which is known to degrade unanchored polyUb chains, reduced VP35 association with Ub and correlated with diminished polymerase activity in a minigenome assay. Using computational methods, we modeled the VP35-Ub non-covalent interacting complex, identified the VP35-Ub interacting surface, and tested mutations to validate the interface. Docking simulations identified chemical compounds that can block VP35-Ub interactions leading to reduced viral polymerase activity. Treatment with the compounds reduced replication of infectious EBOV in cells and in vivo in a mouse model. In conclusion, we identified a novel role of unanchored polyUb in regulating Ebola virus polymerase function and discovered compounds that have promising anti-Ebola virus activity.

Original languageEnglish (US)
Article numbere3002544
JournalPLoS Biology
Volume22
Issue number2
DOIs
StatePublished - Feb 2024
Externally publishedYes

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology
  • General Agricultural and Biological Sciences

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