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Caspase-8 is required for HSV-1-induced apoptosis and promotes effective viral particle release via autophagy inhibition
Regulated cell death (RCD) plays an important role in the progression of viral replication and particle release in cells infected by herpes simplex virus-1 (HSV-1). However, the kind of RCD (apoptosis, necroptosis, others) and the resulting cytopathic effect of HSV-1 depends on the cell type and the...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070401/ https://www.ncbi.nlm.nih.gov/pubmed/36418547 http://dx.doi.org/10.1038/s41418-022-01084-y |
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author | Marino-Merlo, Francesca Klett, Anusha Papaianni, Emanuela Drago, Selene Francesca Anna Macchi, Beatrice Rincón, María Gabriela Andreola, Federica Serafino, Annalucia Grelli, Sandro Mastino, Antonio Borner, Christoph |
author_facet | Marino-Merlo, Francesca Klett, Anusha Papaianni, Emanuela Drago, Selene Francesca Anna Macchi, Beatrice Rincón, María Gabriela Andreola, Federica Serafino, Annalucia Grelli, Sandro Mastino, Antonio Borner, Christoph |
author_sort | Marino-Merlo, Francesca |
collection | PubMed |
description | Regulated cell death (RCD) plays an important role in the progression of viral replication and particle release in cells infected by herpes simplex virus-1 (HSV-1). However, the kind of RCD (apoptosis, necroptosis, others) and the resulting cytopathic effect of HSV-1 depends on the cell type and the species. In this study, we further investigated the molecular mechanisms of apoptosis induced by HSV-1. Although a role of caspase-8 has previously been suggested, we now clearly show that caspase-8 is required for HSV-1-induced apoptosis in a FADD-/death receptor-independent manner in both mouse embryo fibroblasts (MEF) and human monocytes (U937). While wild-type (wt) MEFs and U937 cells exhibited increased caspase-8 and caspase-3 activation and apoptosis after HSV-1 infection, respective caspase-8-deficient (caspase-8−/−) cells were largely impeded in any of these effects. Unexpectedly, caspase-8−/− MEF and U937 cells also showed less virus particle release associated with increased autophagy as evidenced by higher Beclin-1 and lower p62/SQSTM1 levels and increased LC3-I to LC3-II conversion. Confocal and electron microscopy revealed that HSV-1 stimulated a strong perinuclear multivesicular body response, resembling increased autophagy in caspase-8−/− cells, entrapping virions in cellular endosomes. Pharmacological inhibition of autophagy by wortmannin restored the ability of caspase-8−/− cells to release viral particles in similar amounts as in wt cells. Altogether our results support a non-canonical role of caspase-8 in both HSV-1-induced apoptosis and viral particle release through autophagic regulation. |
format | Online Article Text |
id | pubmed-10070401 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-100704012023-04-05 Caspase-8 is required for HSV-1-induced apoptosis and promotes effective viral particle release via autophagy inhibition Marino-Merlo, Francesca Klett, Anusha Papaianni, Emanuela Drago, Selene Francesca Anna Macchi, Beatrice Rincón, María Gabriela Andreola, Federica Serafino, Annalucia Grelli, Sandro Mastino, Antonio Borner, Christoph Cell Death Differ Article Regulated cell death (RCD) plays an important role in the progression of viral replication and particle release in cells infected by herpes simplex virus-1 (HSV-1). However, the kind of RCD (apoptosis, necroptosis, others) and the resulting cytopathic effect of HSV-1 depends on the cell type and the species. In this study, we further investigated the molecular mechanisms of apoptosis induced by HSV-1. Although a role of caspase-8 has previously been suggested, we now clearly show that caspase-8 is required for HSV-1-induced apoptosis in a FADD-/death receptor-independent manner in both mouse embryo fibroblasts (MEF) and human monocytes (U937). While wild-type (wt) MEFs and U937 cells exhibited increased caspase-8 and caspase-3 activation and apoptosis after HSV-1 infection, respective caspase-8-deficient (caspase-8−/−) cells were largely impeded in any of these effects. Unexpectedly, caspase-8−/− MEF and U937 cells also showed less virus particle release associated with increased autophagy as evidenced by higher Beclin-1 and lower p62/SQSTM1 levels and increased LC3-I to LC3-II conversion. Confocal and electron microscopy revealed that HSV-1 stimulated a strong perinuclear multivesicular body response, resembling increased autophagy in caspase-8−/− cells, entrapping virions in cellular endosomes. Pharmacological inhibition of autophagy by wortmannin restored the ability of caspase-8−/− cells to release viral particles in similar amounts as in wt cells. Altogether our results support a non-canonical role of caspase-8 in both HSV-1-induced apoptosis and viral particle release through autophagic regulation. Nature Publishing Group UK 2022-11-24 2023-04 /pmc/articles/PMC10070401/ /pubmed/36418547 http://dx.doi.org/10.1038/s41418-022-01084-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Marino-Merlo, Francesca Klett, Anusha Papaianni, Emanuela Drago, Selene Francesca Anna Macchi, Beatrice Rincón, María Gabriela Andreola, Federica Serafino, Annalucia Grelli, Sandro Mastino, Antonio Borner, Christoph Caspase-8 is required for HSV-1-induced apoptosis and promotes effective viral particle release via autophagy inhibition |
title | Caspase-8 is required for HSV-1-induced apoptosis and promotes effective viral particle release via autophagy inhibition |
title_full | Caspase-8 is required for HSV-1-induced apoptosis and promotes effective viral particle release via autophagy inhibition |
title_fullStr | Caspase-8 is required for HSV-1-induced apoptosis and promotes effective viral particle release via autophagy inhibition |
title_full_unstemmed | Caspase-8 is required for HSV-1-induced apoptosis and promotes effective viral particle release via autophagy inhibition |
title_short | Caspase-8 is required for HSV-1-induced apoptosis and promotes effective viral particle release via autophagy inhibition |
title_sort | caspase-8 is required for hsv-1-induced apoptosis and promotes effective viral particle release via autophagy inhibition |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070401/ https://www.ncbi.nlm.nih.gov/pubmed/36418547 http://dx.doi.org/10.1038/s41418-022-01084-y |
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