Astrovirus replication is dependent on induction of double-membrane vesicles through a PI3K-dependent, LC3-independent pathway.
astrovirus
autophagy
class III PI3K
double-membrane vesicle
replication organelle
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
28 09 2023
28 09 2023
Historique:
medline:
29
9
2023
pubmed:
5
9
2023
entrez:
5
9
2023
Statut:
ppublish
Résumé
Human astrovirus is a positive-sense, single-stranded RNA virus. Astrovirus infection causes gastrointestinal symptoms and can lead to encephalitis in immunocompromised patients. Positive-strand RNA viruses typically utilize host intracellular membranes to form replication organelles, which are potential antiviral targets. Many of these replication organelles are double-membrane vesicles (DMVs). Here, we show that astrovirus infection leads to an increase in DMV formation through a replication-dependent mechanism that requires some early components of the autophagy machinery. Results indicate that the upstream class III phosphatidylinositol 3-kinase (PI3K) complex, but not LC3 conjugation machinery, is utilized in DMV formation. Both chemical and genetic inhibition of the PI3K complex lead to significant reduction in DMVs, as well as viral replication. Elucidating the role of autophagy machinery in DMV formation during astrovirus infection reveals a potential target for therapeutic intervention for immunocompromised patients. IMPORTANCE These studies provide critical new evidence that astrovirus replication requires formation of double-membrane vesicles, which utilize class III phosphatidylinositol 3-kinase (PI3K), but not LC3 conjugation autophagy machinery, for biogenesis. These results are consistent with replication mechanisms for other positive-sense RNA viruses suggesting that targeting PI3K could be a promising therapeutic option for not only astrovirus, but other positive-sense RNA virus infections.
Identifiants
pubmed: 37668367
doi: 10.1128/jvi.01025-23
pmc: PMC10537808
doi:
Substances chimiques
Class III Phosphatidylinositol 3-Kinases
EC 2.7.1.137
Phosphatidylinositol 3-Kinase
EC 2.7.1.137
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0102523Subventions
Organisme : NIAID NIH HHS
ID : R03 AI166434
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA021765
Pays : United States
Organisme : NIAID NIH HHS
ID : K22 AI156116
Pays : United States
Commentaires et corrections
Type : UpdateOf
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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