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.

LXR-inducible host E3 ligase IDOL targets a human cytomegalovirus reactivation determinant

“…The expression of HSV-1 ICP0, a critical protein for reactivation and replication, is suppressed by the host neuronal microRNA-138 to facilitate latency (95, 96). Moreover, ICP0 was recently shown to be regulated by the host E3 ligase, TRIM23, which is in turn, countered by the HSV-1 late protein, γ 1 34.5 (97). While speculative, TRIM23 may moderate ICP0 protein levels to suppress reactivation, where γ 1 34.5 ensures the commitment to replication by blocking TRIM23-mediated turnover of ICP0.…”

Forsythoside A inhibits apoptosis and autophagy induced by infectious bronchitis virus through regulation of the PI3K/Akt/NF-κB pathway

“…The IBV strain Beaudette US (Cat No. VR-22) was obtained from the ATCC ( 11 , 24 ), amplified and titrated in BHK and Vero cells. BHK cells were cultured in DMEM which was supplemented with 10% FBS and 1% PS for 24 h and then infected with 10 TCID 50 of IBV and periodic rocking.…”

The precise function of alphaherpesvirus tegument proteins and their interactions during the viral life cycle

“…Some herpesviruses have strategies to regulate autophagy, and many rely on cellular autophagy mechanisms to successfully complete their life cycle ( Yin et al, 2017 ; Xu et al, 2018 ). Examples include pUL21 ( Ma et al, 2023 )and VP16 ( Ming et al, 2022 )for PRV and ICP34.5 ( Tallóczy et al, 2006 ; Ripa et al, 2022 ), pUS11 ( Lussignol and Esclatine, 2017 ) and ICP0 ( Liu et al, 2021 ; Waisner et al, 2023 ) for HSV-1. ICP34.5 is the first-discovered anti-autophagy viral protein of herpesviruses ( Tallóczy et al, 2002 ).…”

“…ICP34.5 is the first-discovered anti-autophagy viral protein of herpesviruses ( Tallóczy et al, 2002 ). The ability to control autophagy by interacting with BECN1 is necessary for HSV-1 neurovirulence ( Orvedahl et al, 2007 ); pUL21, a recently discovered herpesvirus protein associated with autophagy, triggers cGAS degradation through Tollip-mediated selective autophagy, thereby inhibiting innate immunity ( Ma et al, 2023 ); and the host E3 ligase TRIM23, which induces autophagy to limit HSV-1 replication (and that of additional viruses), triggers proteasomal degradation of ICP0 through ubiquitination of K11 and K48 interactions ( Liu et al, 2021 ). The major autophagy adaptor proteins Sequestosome 1 and Optineurin are downregulated in the early stages of HSV-1 infection ( Waisner and Kalamvoki, 2019 ).…”