Dataset Information

Interaction With 14-3-3 Correlates With Inactivation of the RIG-I Signalosome by Herpesvirus Ubiquitin Deconjugases.

ABSTRACT: The hijacking of cellular function through expression of proteins that interfere with the activity of cellular enzymes and regulatory complexes is a common strategy used by viruses to remodel the cell environment in favor of their own replication and spread. Here we report that the ubiquitin deconjugases encoded in the N-terminal domain of the large tegument proteins of Epstein-Barr virus (EBV), Kaposi Sarcoma herpesvirus (KSHV) and human cytomegalovirus (HCMV), but not herpes simplex virus-1 (HSV-1), target an early step of the IFN signaling cascade that involves the formation of a trimolecular complex with the ubiquitin ligase TRIM25 and the 14-3-3 molecular scaffold. Different from other homologs, the HSV-1 encoded enzyme fails to interact with 14-3-3, which correlates with failure to promote the autoubiquitination and sequestration of TRIM25 in cytoplasmic aggregates, and inability to block the activation and nuclear translocation of the IRF3 transcription factor. These findings highlight a key role for 14-3-3 molecular scaffolds in the regulation of innate immune response to herpesvirus infections and points to a possible target for the development of a new type of antivirals with applications in a broad spectrum of human diseases.

SUBMITTER: Gupta S

PROVIDER: S-EPMC7080818 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Interaction With 14-3-3 Correlates With Inactivation of the RIG-I Signalosome by Herpesvirus Ubiquitin Deconjugases.

Gupta Soham S Ylä-Anttila Päivi P Sandalova Tatyana T Achour Adnane A Masucci Maria G MG

Frontiers in immunology 20200312

The hijacking of cellular function through expression of proteins that interfere with the activity of cellular enzymes and regulatory complexes is a common strategy used by viruses to remodel the cell environment in favor of their own replication and spread. Here we report that the ubiquitin deconjugases encoded in the N-terminal domain of the large tegument proteins of Epstein-Barr virus (EBV), Kaposi Sarcoma herpesvirus (KSHV) and human cytomegalovirus (HCMV), but not herpes simplex virus-1 (H ...[more]

PMID: 32226432

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Project description:The N-terminal domains of the herpesvirus large tegument proteins encode a conserved cysteine protease with ubiquitin- and NEDD8-specific deconjugase activity. The proteins are expressed during the productive virus cycle and are incorporated into infectious virus particles, being delivered to the target cells upon primary infection. Members of this viral enzyme family were shown to regulate different aspects of the virus life cycle and the innate anti-viral response. However, only few substrates have been identified and the mechanisms of these effects remain largely unknown. In order to gain insights on the substrates and signaling pathways targeted by the viral enzymes, we have used co-immunoprecipitation and mass spectrometry to identify cellular proteins that interact with the Epstein-Barr virus encoded homologue BPLF1. Several members of the 14-3-3-family of scaffold proteins were found amongst the top hits of the BPLF1 interactome, suggesting that, through this interaction, BPLF1 may regulate a variety of cellular signaling pathways. Analysis of the shared protein-interaction network revealed that BPLF1 promotes the assembly of a tri-molecular complex including, in addition to 14-3-3, the ubiquitin ligase TRIM25 that participates in the innate immune response via ubiquitination of cytosolic pattern recognition receptor, RIG-I. The involvement of BPLF1 in the regulation of this signaling pathway was confirmed by inhibition of the type-I IFN responses in cells transfected with a catalytically active BPLF1 N-terminal domain or expressing the endogenous protein upon reactivation of the productive virus cycle. We found that the active viral enzyme promotes the dimerization and autoubiquitination of TRIM25. Upon triggering of the IFN response, RIG-I is recruited to the complex but ubiquitination is severely impaired, which functionally inactivates the RIG-I signalosome. The capacity to bind to and functionally inactivate the RIG-I signalosome is shared by the homologues encoded by other human herpesviruses.

Dataset Information

Interaction With 14-3-3 Correlates With Inactivation of the RIG-I Signalosome by Herpesvirus Ubiquitin Deconjugases.

Publications

Interaction With 14-3-3 Correlates With Inactivation of the RIG-I Signalosome by Herpesvirus Ubiquitin Deconjugases.

Similar Datasets

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