Autolysosomes and caspase-3 control the biogenesis and release of immunogenic apoptotic exosomes.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
11 02 2022
11 02 2022
Historique:
received:
16
07
2021
accepted:
27
01
2022
revised:
04
01
2022
entrez:
12
2
2022
pubmed:
13
2
2022
medline:
9
4
2022
Statut:
epublish
Résumé
Apoptotic exosome-like vesicles (ApoExos) are a novel type of extracellular vesicle that contribute to the propagation of inflammation at sites of vascular injury when released by dying cells. ApoExos are characterized by the presence of the C-terminal perlecan LG3 fragment and 20S proteasome, and they are produced downstream of caspase-3 activation. In the present study, we assessed the relative roles of autophagy and caspase-3-mediated pathways in controlling the biogenesis and secretion of immunogenic ApoExos. Using electron microscopy and confocal immunofluorescence microscopy in serum-starved endothelial cells, we identified large autolysosomes resulting from the fusion of lysosomes, multivesicular bodies, and autophagosomes as a site of ApoExo biogenesis. Inhibition of autophagy with ATG7 siRNA or biochemical inhibitors (wortmannin and bafilomycin) coupled with proteomics analysis showed that autophagy regulated the processing of perlecan into LG3 and its loading onto ApoExos but was dispensable for ApoExo biogenesis. Caspase-3 activation was identified using caspase-3-deficient endothelial cells or caspase inhibitors as a pivotal regulator of fusion events between autolysosomes and the cell membrane, therefore regulating the release of immunogenic ApoExos. Collectively, these findings identified autolysosomes as a site of ApoExo biogenesis and caspase-3 as a crucial regulator of autolysosome cell membrane interactions involved in the secretion of immunogenic ApoExos.
Identifiants
pubmed: 35149669
doi: 10.1038/s41419-022-04591-5
pii: 10.1038/s41419-022-04591-5
pmc: PMC8837616
doi:
Substances chimiques
Caspase 3
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
145Subventions
Organisme : Gouvernement du Canada | Instituts de Recherche en Santé du Canada | Institute of Nutrition, Metabolism and Diabetes (Institut de la Nutrition, du Métabolisme et du Diabète)
ID : MOP-15447
Organisme : Gouvernement du Canada | Instituts de Recherche en Santé du Canada | Institute of Nutrition, Metabolism and Diabetes (Institut de la Nutrition, du Métabolisme et du Diabète)
ID : PJT-148884
Informations de copyright
© 2022. The Author(s).
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