BIKE regulates dengue virus infection and is a cellular target for broad-spectrum antivirals.
Adaptor Proteins, Vesicular Transport
/ antagonists & inhibitors
Animals
Antiviral Agents
/ pharmacology
Cell Line
Chlorocebus aethiops
Dengue
/ drug therapy
Dengue Virus
/ drug effects
Drug Repositioning
Host Microbial Interactions
Humans
Intracellular Signaling Peptides and Proteins
/ physiology
Lactones
/ pharmacology
Phosphorylation
Protein Kinase Inhibitors
/ pharmacology
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
RNA, Viral
Recombinant Proteins
Resorcinols
/ pharmacology
Signal Transduction
Transcription Factors
/ physiology
Vero Cells
Virus Internalization
Virus Replication
Antivirals
Dengue virus
Drug repurposing
Kinase inhibitors
Virus-host interactions
Journal
Antiviral research
ISSN: 1872-9096
Titre abrégé: Antiviral Res
Pays: Netherlands
ID NLM: 8109699
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
09
06
2020
revised:
07
10
2020
accepted:
26
10
2020
pubmed:
3
11
2020
medline:
27
7
2021
entrez:
2
11
2020
Statut:
ppublish
Résumé
Global health is threatened by emerging viruses, many of which lack approved therapies and effective vaccines, including dengue, Ebola, and Venezuelan equine encephalitis. We previously reported that AAK1 and GAK, two of the four members of the understudied Numb-associated kinases (NAK) family, control intracellular trafficking of RNA viruses. Nevertheless, the role of BIKE and STK16 in viral infection remained unknown. Here, we reveal a requirement for BIKE, but not STK-16, in dengue virus (DENV) infection. BIKE mediates both early (postinternalization) and late (assembly/egress) stages in the DENV life cycle, and this effect is mediated in part by phosphorylation of a threonine 156 (T156) residue in the μ subunit of the adaptor protein (AP) 2 complex. Pharmacological compounds with potent anti-BIKE activity, including the investigational anticancer drug 5Z-7-oxozeaenol and more selective inhibitors, suppress DENV infection both in vitro and ex vivo. BIKE overexpression reverses the antiviral activity, validating that the mechanism of antiviral action is, at least in part, mediated by BIKE. Lastly, 5Z-7-oxozeaenol exhibits antiviral activity against viruses from three unrelated RNA viral families with a high genetic barrier to resistance. These findings reveal regulation of poorly understood stages of the DENV life cycle via BIKE signaling and establish a proof-of-principle that pharmacological inhibition of BIKE can be potentially used as a broad-spectrum strategy against acute emerging viral infections.
Identifiants
pubmed: 33137362
pii: S0166-3542(20)30380-6
doi: 10.1016/j.antiviral.2020.104966
pmc: PMC7879702
mid: NIHMS1666103
pii:
doi:
Substances chimiques
7-oxozeanol
0
AP2M1 protein, human
0
Adaptor Proteins, Vesicular Transport
0
Antiviral Agents
0
Intracellular Signaling Peptides and Proteins
0
Lactones
0
Protein Kinase Inhibitors
0
RNA, Viral
0
Recombinant Proteins
0
Resorcinols
0
Transcription Factors
0
AAK1 protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
STK16 protein, human
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
104966Subventions
Organisme : NIAID NIH HHS
ID : U19 AI109662
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000093
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR003142
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000090
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.
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