Initial Contact: The First Steps in Herpesvirus Entry

Azab, Walid; Osterrieder, Nikolaus

doi:10.1007/978-3-319-53168-7_1

Cited by 25 publications

(24 citation statements)

References 157 publications

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“…During viral infection, the virus is recognized by pathogen recognition receptors of infected cells, which trigger signaling cascades to initiate innate intracellular antiviral defenses and to restrict viral replication (29)(30)(31)(32). Three protein degradation systems (the ubiquitin-proteasome system [UPS], lysosomes, and the autophagy system) contribute to the maintenance of protein homeostasis, as well as antiviral defenses against different viral infections (33,34).…”

Section: Discussionmentioning

confidence: 99%

Porcine MKRN1 Modulates the Replication and Pathogenesis of Porcine Circovirus Type 2 by Inducing Capsid Protein Ubiquitination and Degradation

Wang

et al. 2018

J Virol

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Porcine circovirus type 2 (PCV2) capsid protein (Cap) is a unique structure protein that plays pivotal roles in the process of viral replication and pathogenesis. Herein, we characterized a putative porcine Makorin RING finger protein 1 (pMKRN1) variant, an N-terminal-truncated variant of putative full-size porcine MKRN1 which has a unique expression pattern resulting from the porcine gene and which interacts with PCV2 Cap. A domain mapping assay showed that the C terminus of pMKRN1 and fragments (amino acids 108 to 198) of Cap are required for this interaction. PCV2 transiently upregulated pMKRN1 in PK-15 cells, but persistent viral infection downregulated pMKRN1 in major pathological tissues of PCV2-infected piglets. Overexpression of pMKRN1 significantly inhibited the generation of progeny PCV2 via ubiquitination and degradation of Cap, whereas knockout of pMKRN1 blocked Cap degradation and promoted progeny virus replication. pMKRN1 specifically targeted PCV2 Cap lysine residues 164, 179, and 191 to induce polyubiquitination and subsequent degradation. Mutation of either of the three lysine residues in the Cap protein or mutation of the histidine at residue 243 within the RING finger domain of pMKRN1 abrogated the E3 ligase activity of pMKRN1, rendering cells incapable of inducing Cap ubiquitination and degradation. Consistent with this finding, a Cap ubiquitination-deficient PCV2 strain showed enhanced virus replication and produced severe histological lesions in the lung and lymph node tissues compared with wild-type PCV2. Taken together, the results presented here suggest that PCV2 downregulates the pMKRN1 variant to avoid pMKRN1-mediated Cap ubiquitination and degradation, thus promoting viral replication and pathogenesis in its targeted tissues. Porcine circovirus type 2 is the pathogen to which pigs are the most susceptible, causing immense economic losses in the global swine industry, but whether host cells have developed some strategies to prevent viral replication is still unclear. Here, we found that porcine MKRN1 (pMKRN1) was upregulated in the early stage of PCV2 infection and mediated the polyubiquitination and degradation of Cap protein to block PCV2 replication, yet persistent PCV2 infection downregulated pMKRN1 levels to avoid degradation, promoting viral replication and pathogenesis in its targeted tissues. These data present new insight into the molecular mechanisms underlying the antiviral effects of pMKRN1 E3 ligase during PCV2 infection and also suggest potential new control measures for PCV2 outbreaks.

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Section: Discussionmentioning

confidence: 99%

Porcine MKRN1 Modulates the Replication and Pathogenesis of Porcine Circovirus Type 2 by Inducing Capsid Protein Ubiquitination and Degradation

Wang

et al. 2018

J Virol

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“…Thus HVEM/HveA, Nectin-1/HveC and 3-OS HS are receptors for gD, PILRα, MAG and NMHC-IIA and B are bound by gB, and gH/gL interact with integrins [5,109,[112][113][114][115]. This multipartite system allows the virus to penetrate via two different pathways-by fusion at the plasma membrane or by endocytosis [4,[116][117][118].…”

Section: Tropism Retargeted Unattenuated Ohsvsmentioning

confidence: 99%

Herpes Simplex Virus Oncolytic Immunovirotherapy: The Blossoming Branch of Multimodal Therapy

Menotti

Avitabile

2020

IJMS

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Oncolytic viruses are smart therapeutics against cancer due to their potential to replicate and produce the needed therapeutic dose in the tumor, and to their ability to self-exhaust upon tumor clearance. Oncolytic virotherapy strategies based on the herpes simplex virus are reaching their thirties, and a wide variety of approaches has been envisioned and tested in many different models, and on a range of tumor targets. This huge effort has culminated in the primacy of an oncolytic HSV (oHSV) being the first oncolytic virus to be approved by the FDA and EMA for clinical use, for the treatment of advanced melanoma. The path has just been opened; many more cancer types with poor prognosis await effective and innovative therapies, and oHSVs could provide a promising solution, especially as combination therapies and immunovirotherapies. In this review, we analyze the most recent advances in this field, and try to envision the future ahead of oHSVs.

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“…As mentioned above, the fusion process is mediated by a set of interactions between gD, gH/gL, and gB, and between these glycoproteins and their receptors (Azab and Osterrieder, 2017;Weed and Nicola, 2017), thus multiple glycoprotein or RBSs are potential to be targets of HSV inactivators. Taking the potent gH/gL-specific neutralizing antibody as the example, it could inhibit the formation of the gB-gH/gL complex, suggesting that the gB binding site in gH/gL may locate in the vicinity of the neutralizing epitope (Chowdary et al, 2010;Bohm et al, 2016).…”

Section: Protein-and Peptide-based Hsv Inactivatorsmentioning

confidence: 99%

Protein- and Peptide-Based Virus Inactivators: Inactivating Viruses Before Their Entry Into Cells

Wang

Wen

et al. 2020

Front. Microbiol.

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Infectious diseases caused by human immunodeficiency virus (HIV) and other highly pathogenic enveloped viruses, have threatened the global public health. Most antiviral drugs act as passive defenders to inhibit viral replication inside the cell, while a few of them function as gate keepers to combat viruses outside the cell, including fusion inhibitors, e.g., enfuvirtide, and receptor antagonists, e.g., maraviroc, as well as virus inactivators (including attachment inhibitors). Different from fusion inhibitors and receptor antagonists that must act in the presence of target cells, virus inactivators can actively inactivate cell-free virions in the blood, through interaction with one or more sites in the envelope glycoproteins (Envs) on virions. Notably, a number of protein-and peptide-based virus inactivators (PPVIs) under development are expected to have a better utilization rate than the current antiviral drugs and be safer for in vivo human application than the chemical-based virus inactivators. Here we have highlighted recent progress in developing PPVIs against several important enveloped viruses, including HIV, influenza virus, Zika virus (ZIKV), dengue virus (DENV), and herpes simplex virus (HSV), and the potential use of PPVIs for urgent treatment of infection by newly emerging or re-emerging viruses.

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Initial Contact: The First Steps in Herpesvirus Entry

Cited by 25 publications

References 157 publications

Porcine MKRN1 Modulates the Replication and Pathogenesis of Porcine Circovirus Type 2 by Inducing Capsid Protein Ubiquitination and Degradation

Porcine MKRN1 Modulates the Replication and Pathogenesis of Porcine Circovirus Type 2 by Inducing Capsid Protein Ubiquitination and Degradation

Herpes Simplex Virus Oncolytic Immunovirotherapy: The Blossoming Branch of Multimodal Therapy

Protein- and Peptide-Based Virus Inactivators: Inactivating Viruses Before Their Entry Into Cells

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