14-3-3 scaffold proteins mediate the inactivation of trim25 and inhibition of the type I interferon response by herpesvirus deconjugases

English version

Autoři: Soham Gupta ^aff001; Päivi Ylä-Anttila ^aff001; Tatyana Sandalova ^aff002; Renhua Sun ^aff002; Adnane Achour ^aff002; Maria G. Masucci ^aff001
Působiště autorů: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden ^aff001; Science for Life Laboratory, Campus Solna, Stockholm, Sweden ^aff002; Department of Medicine, Karolinska Institute, Stockholm, Sweden ^aff003; Division of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden ^aff004
Vyšlo v časopise: 14-3-3 scaffold proteins mediate the inactivation of trim25 and inhibition of the type I interferon response by herpesvirus deconjugases. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1008146
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008146

Souhrn

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 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.

Klíčová slova:

Crystal structure – Dimers – HeLa cells – Immunoprecipitation – Transfection – Ubiquitination – Ligases

Zdroje

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