TNRC6 proteins modulate hepatitis C virus replication by spatially regulating the binding of miR-122/Ago2 complexes to viral RNA.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
09 07 2019
09 07 2019
Historique:
accepted:
16
04
2019
revised:
03
04
2019
received:
13
10
2018
pubmed:
19
4
2019
medline:
26
2
2020
entrez:
19
4
2019
Statut:
ppublish
Résumé
The liver-specific microRNA, miR-122, is an essential host factor for replication of the hepatitis C virus (HCV). miR-122 stabilizes the positive-strand HCV RNA genome and promotes its synthesis by binding two sites (S1 and S2) near its 5' end in association with Ago2. Ago2 is essential for both host factor activities, but whether other host proteins are involved is unknown. Using an unbiased quantitative proteomics screen, we identified the TNRC6 protein paralogs, TNRC6B and TNRC6C, as functionally important but redundant components of the miR-122/Ago2 host factor complex. Doubly depleting TNRC6B and TNRC6C proteins reduced HCV replication in human hepatoma cells, dampening miR-122 stimulation of viral RNA synthesis without reducing the stability or translational activity of the viral RNA. TNRC6B/C were required for optimal miR-122 host factor activity only when S1 was able to bind miR-122, and restricted replication when S1 was mutated and only S2 bound by miR-122. TNRC6B/C preferentially associated with S1, and TNRC6B/C depletion enhanced Ago2 association at S2. Collectively, these data suggest a model in which TNRC6B/C regulate the assembly of miR-122/Ago complexes on HCV RNA, preferentially directing miR-122/Ago2 to S1 while restricting its association with S2, thereby fine-tuning the spatial organization of miR-122/Ago2 complexes on the viral genome.
Identifiants
pubmed: 30997501
pii: 5475080
doi: 10.1093/nar/gkz278
pmc: PMC6614814
doi:
Substances chimiques
5' Untranslated Regions
0
AGO2 protein, human
0
Argonaute Proteins
0
MIRN122 microRNA, human
0
MicroRNAs
0
RNA, Viral
0
RNA-Binding Proteins
0
TNRC6B protein, human
0
TNRC6C protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
6411-6424Subventions
Organisme : NCI NIH HHS
ID : P30 CA016086
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI095690
Pays : United States
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
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