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Caspase-8 is required for HSV-1-induced apoptosis and promotes effective viral particle release via autophagy inhibition.
- Source :
-
Cell death and differentiation [Cell Death Differ] 2023 Apr; Vol. 30 (4), pp. 885-896. Date of Electronic Publication: 2022 Nov 24. - Publication Year :
- 2023
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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.<br /> (© 2022. The Author(s).)
Details
- Language :
- English
- ISSN :
- 1476-5403
- Volume :
- 30
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cell death and differentiation
- Publication Type :
- Academic Journal
- Accession number :
- 36418547
- Full Text :
- https://doi.org/10.1038/s41418-022-01084-y