Herpesvirus-mediated stabilization of ICP0 expression neutralizes restriction by TRIM23.

Abstract

Herpes simplex virus (HSV) infection relies on immediate early proteins that initiate viral replication. Among them, ICP0 is known, for many years, to facilitate the onset of viral gene expression and reactivation from latency. However, how ICP0 itself is regulated remains elusive. Through genetic analyses, we identify that the viral γ134.5 protein, an HSV virulence factor, interacts with and prevents ICP0 from proteasomal degradation. Furthermore, we show that the host E3 ligase TRIM23, recently shown to restrict the replication of HSV-1 (and certain other viruses) by inducing autophagy, triggers the proteasomal degradation of ICP0 via K11- and K48-linked ubiquitination. Functional analyses reveal that the γ134.5 protein binds to and inactivates TRIM23 through blockade of K27-linked TRIM23 autoubiquitination. Deletion of γ134.5 or ICP0 in a recombinant HSV-1 impairs viral replication, whereas ablation of TRIM23 markedly rescues viral growth. Herein, we show that TRIM23, apart from its role in autophagy-mediated HSV-1 restriction, down-regulates ICP0, whereas viral γ134.5 functions to disable TRIM23. Together, these results demonstrate that posttranslational regulation of ICP0 by virus and host factors determines the outcome of HSV-1 infection.

• Authors: Xing Liu, Dhiraj Acharya, Eric Krawczyk, Chase Kangas, Michaela U Gack, Bin He
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 51 (12 21 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 34903664 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Viral
• Immediate-Early Proteins
• TRIM23 protein, human
• Ubiquitin-Protein Ligases
• Vmw110 protein, Human herpesvirus 1
• Protein Serine-Threonine Kinases
• TBK1 protein, human
• GTP-Binding Proteins

Topics

• Animals
• Antibodies, Viral
• Cell Line
• GTP-Binding Proteins (genetics, metabolism)
• Gene Expression Regulation, Viral
• Herpesvirus 1, Human (physiology)
• Host-Pathogen Interactions (physiology)
• Humans
• Immediate-Early Proteins (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Virus Replication