Caspase-8 is required for HSV-1-induced apoptosis and promotes effective viral particle release via autophagy inhibition

Abstract: 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

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Cell death and differentiation. - 30, 4 (2023) , 885-896, ISSN: 1476-5403

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2022
• Creator: 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

Further information

• DOI: 10.1038/s41418-022-01084-y
• URN: urn:nbn:de:bsz:25-freidok-2313838
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:42 PM CET