14-3-3 scaffold proteins mediate the inactivation of trim25 and inhibition of the type I interferon response by herpesvirus deconjugases.
The 14-3-3 molecular scaffolds promote type I interferon (IFN) responses by stabilizing the interaction of RIG-I with the TRIM25 ligase. Viruses have evolved unique strategies to halt this cellular response to support their replication and spread. Here, we report that the ubiquitin deconjugase (DUB) encoded in the N-terminus of the ... Epstein-Barr virus (EBV) large tegument protein BPLF1 harnesses 14-3-3 molecules to promote TRIM25 autoubiquitination and sequestration of the ligase into inactive protein aggregates. Catalytically inactive BPLF1 induced K48-linked autoubiquitination and degradation of TRIM25 while the ligase was mono- or di-ubiquitinated in the presence of the active viral enzyme and formed cytosolic aggregates decorated by the autophagy receptor p62/SQSTM1. Aggregate formation and the inhibition of IFN response were abolished by mutations of solvent exposed residues in helix-2 of BPLF1 that prevented binding to 14-3-3 while preserving both catalytic activity and binding to TRIM25. 14-3-3 interacted with the Coiled-Coil (CC) domain of TRIM25 in in vitro pulldown, while BPLF1 interacted with both the CC and B-box domains, suggesting that 14-3-3 positions BPLF1 at the ends of the CC dimer, close to known autoubiquitination sites. Our findings provide a molecular understanding of the mechanism by which a viral deubiquitinase inhibits the IFN response and emphasize the role of 14-3-3 proteins in modulating antiviral defenses.
Mesh Terms:
14-3-3 Proteins, Antiviral Agents, HeLa Cells, Herpesviridae, Herpesviridae Infections, Humans, Immunity, Innate, Interferon Type I, Protein Binding, Proteolysis, Signal Transduction, Transcription Factors, Tripartite Motif Proteins, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination, Viral Regulatory and Accessory Proteins, Virus Replication
14-3-3 Proteins, Antiviral Agents, HeLa Cells, Herpesviridae, Herpesviridae Infections, Humans, Immunity, Innate, Interferon Type I, Protein Binding, Proteolysis, Signal Transduction, Transcription Factors, Tripartite Motif Proteins, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination, Viral Regulatory and Accessory Proteins, Virus Replication
PLoS Pathog.
Date: Dec. 01, 2018
PubMed ID: 31710640
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