Viral entry and the ubiquitin‐proteasome system

Schneider, Seth M.; Lee, Becky H.; Nicola, Anthony V.

doi:10.1111/cmi.13276

Cited by 31 publications

(27 citation statements)

References 123 publications

(182 reference statements)

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“…However, no evidence has been reported that the latter involves ubiquitination. Taken together with the finding that MG-132 inhibits capsid motility towards the nucleus (61, 62), this is consistent with a role of ubiquitin during virus entry (reviewed in (63)). However, there is conflicting evidence regarding the activity of MG-132 during early HSV-1 infection (64).…”

Section: Discussionsupporting

confidence: 81%

pUL36 de-ubiquitinase activity augments both the initiation and progression of lytic virus infection in IFN–primed cells

Mohnke

Stark

Fischer

et al. 2021

Preprint

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The conserved, structural HSV-1 tegument protein pUL36 is essential for both virus entry and assembly. While its N-terminal de-ubiquitinase (DUB) activity is dispensable for infection in cell culture, it is required for efficient virus spread in vivo by acting as a potent viral immune evasin. Here, we show that the pUL36 DUB activity was required to overcome interferon-(IFN)-mediated suppression of both plaque initiation and progression to productive infection. Immediately upon virus entry, incoming tegument-derived pUL36-DUB activity helped the virus to escape intrinsic antiviral resistance and efficiently initiate lytic virus replication in IFN-primed cells. Subsequently, de novo expressed pUL36-DUB augmented the efficiency of productive infection and virus yield. Interestingly, removal of IFN shortly after inoculation only resulted in a partial rescue of plaque formation, indicating that an IFN-induced defense mechanism eliminates invading virus particles unless counteracted by pUL36-DUB activity. Taken together, we demonstrated that the pUL36 DUB disarms IFN-induced antiviral responses at two levels, namely, to protect the infectivity of invading virus as well as to augment productive virus replication in IFN-primed cells.Author SummaryHSV-1 is an ubiquitous human pathogen that is responsible for common cold sores but may also cause life-threatening disease. pUL36 is an essential and conserved protein of infectious herpesvirus virions with a unique de-ubiquitinating (DUB) activity. The pUL36 DUB is dispensable for efficient virus infection in cell culture but represents an important viral immune evasin in vivo. Here, we showed that tegument-derived DUB activity delivered by the invading virus particles is required to overcome IFN-induced host resistance and to initiate efficient lytic infection. De novo expressed pUL36 DUB subsequently augments productive infection and virus yield. These data indicate that the pUL36 DUB antagonizes the activity of yet unidentified IFN-inducible E3 ligases to facilitate productive infection at multiple levels. Our findings underscore the therapeutic potential of targeting conserved herpesvirus DUBs to prevent or treat herpesvirus disease.

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Section: Discussionsupporting

confidence: 81%

pUL36 de-ubiquitinase activity augments both the initiation and progression of lytic virus infection in IFN–primed cells

Mohnke

Stark

Fischer

et al. 2021

Preprint

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“…Examples are the ESCRT-III co-factor VPS4 (Cabrera et al ., 2019; Crump et al ., 2007), EIF4H (Page & Read, 2010), the Kif2a subunit of kinesin-13 (Turan et al ., 2019), the POLR1C subunit of RNA polymerase III (Carter-Timofte et al ., 2018), the DNA protein kinase PRKDC (Justice et al ., 2021), and DDX1 (Zhang et al ., 2011). Moreover, the deubiquitinase USP7 (Rodriguez et al ., 2020) and the ubiquitin ligases RNF123, TRIM72, UFC1 and UBE3A as well as the proteasome might regulate capsid functionality (Huffmaster et al ., 2015; Schneider et al ., 2021) or their degradation(Horan et al ., 2013; Sun et al ., 2019). These data show that HSV-1 capsids exposing a different tegument composition recruited specific cytosolic proteins from resting or IFN-induced macrophages.…”

Section: Resultsmentioning

confidence: 99%

The interferon-inducible GTPase MxB promotes capsid disassembly and genome release of herpesviruses

Sodeik

Serrero²,

Girault

et al. 2022

Preprint

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Host proteins sense viral products and induce defence mechanisms, particularly in immune cells. Using cell-free assays and quantitative mass spectrometry, we determined the interactome of capsid-host protein complexes of herpes simplex virus and identified the large dynamin-like GTPase myxovirus resistance protein B (MxB) as an interferon-inducible protein interacting with capsids. Electron microscopy analyses showed that cytosols containing MxB had the remarkable capability to disassemble the icosahedral capsids of herpes simplex viruses and varicella zoster virus into flat sheets of connected triangular faces. In contrast, capsids remained intact in cytosols with MxB mutants unable to hydrolyse GTP or to dimerize. Our data suggest that MxB senses herpesviral capsids, mediates their disassembly, and thereby restricts the efficiency of nuclear targeting of incoming capsids and/or the assembly of progeny capsids. The resulting premature release of viral genomes from capsids may enhance the activation of DNA sensors, and thereby amplify the innate immune responses.

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“…In addition, we found that proteasome signaling pathway was also significantly enriched in multiple groups of DEGs (0 hpi vs. 20 hpi, 12 hpi vs. 20 hpi, and 6 hpi vs. 12 hpi). Viruses confiscate cellular components of the proteasome to facilitate many aspects of the infectious cycle ( van Tol et al, 2017 ; Schneider et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Dual RNA-Seq of H5N1 Avian Influenza Virus and Host Cell Transcriptomes Reveals Novel Insights Into Host-Pathogen Cross Talk

Wang

Zhang

et al. 2022

Front. Microbiol.

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H5N1 avian influenza virus (AIV) is a highly pathogenic influenza virus that poses a substantial threat to poultry production and public health. A comprehensive understanding of host–pathogen interactions for AIV requires knowledge of gene expression changes in both the pathogen and the host upon infection. We report the use of dual RNA sequencing technology to uncover trends in gene expression in H5N1 AIV and chickens (DF1 cells) during the course of infection. The expression of all viral genes increased continuously from 0 to 20 h post infection. We also identified 2,762 differentially expressed host genes during infection. Pathway analysis found that genes related to the signaling pathways of DNA replication, T cell activation, NF-kappa B signaling pathway, and RNA degradation were significantly enriched. We demonstrated that the cis-acting lncRNA MSTRG.14019.1 targeted CSE1L and may affect virus replication. This study provides a more comprehensive and detailed understanding of host-virus interactions at the RNA level during the course of H5N1 AIV infection.

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Viral entry and the ubiquitin‐proteasome system

Cited by 31 publications

References 123 publications

pUL36 de-ubiquitinase activity augments both the initiation and progression of lytic virus infection in IFN–primed cells

pUL36 de-ubiquitinase activity augments both the initiation and progression of lytic virus infection in IFN–primed cells

The interferon-inducible GTPase MxB promotes capsid disassembly and genome release of herpesviruses

Dual RNA-Seq of H5N1 Avian Influenza Virus and Host Cell Transcriptomes Reveals Novel Insights Into Host-Pathogen Cross Talk

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