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.
Highlights
Post-translational modifications by covalent conjugation of ubiquitin and ubiquitin-like polypeptides play a key role in the regulation of a variety of cellular functions including the cellular and organismal response to infection [1]
We have previously reported that the catalytic domain of the Epstein-Barr virus (EBV) large tegument protein BPLF1 inhibits IFN signaling by inducing the formation of a trimolecular complex including 14-3-3 and the ubiquitin ligase TRIM25, which correlates with failure to ubiquitinate RIG-I and functional inactivation of the RIG-I signalosome [7, 18]
In order to investigate whether this property is shared by the homologs encoded by other herpesviruses, HeLa cells were transfected with the FLAGtagged versions of the catalytic domains of EBV-BPLF1, HSVUL36, human cytomegalovirus (HCMV)-UL48, and Kaposi Sarcoma herpesvirus (KSHV)-ORF64 and the formation of endogenous TRIM25 aggregates was monitored 24 h after transfection by staining with antibodies specific for TRIM25
Summary
Post-translational modifications by covalent conjugation of ubiquitin and ubiquitin-like polypeptides play a key role in the regulation of a variety of cellular functions including the cellular and organismal response to infection [1]. Following recognition of viral nucleic acids by members of the RIG-I-like receptor family, ubiquitination-dependent events mediates the transcriptional activation of type I interferon (IFN) that regulates the expression of a variety of IFN-stimulated genes (ISGs) whose products inhibit virus replication and decrease the cell susceptibility to infection [3]. Ubiquitination of the RIG-I family members by tripartite motif (TRIM) E3 ligases is a critical step in this signaling cascade that is often targeted by viruses. Failure to ubiquitinate RIG-I prevents its translocation to Mitochondrial Anti-Viral Signaling proteins (MAVS), blocking downstream events that, via recruitment of TNF-Receptor Associate Factor (TRAF)-3 and the TRAF family memberassociated NF-kappa B activator (TANK), trigger the activation of TANK binding kinase-1 (TBK1), and I-kappa B kinase epsilon (IKK-epsilon) that phosphorylate IRF3 and IRF7 [6]
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