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CCR4-NOT differentially controls host versus virus poly(a)-tail length and regulates HCMV infection
Hannah M Burgess1,2, Rebecca Grande2, Sofia Riccio1
1Department of Microbial Sciences, University of Surrey, Guildford, UK.
EMBO Reports
|October 17, 2023
Summary
Human cytomegalovirus (HCMV) remodels host gene expression without mRNA decay enzymes. Host factors CNOT1 and CNOT3 are crucial for HCMV replication by regulating viral mRNA poly(A)-tails.
Area of Science:
- Virology
- Molecular Biology
- Gene Expression Regulation
Background:
- Most viruses induce mRNA decay, but human cytomegalovirus (HCMV) remodels the translatome differently.
- HCMV infection alters host gene expression without producing its own mRNA decay enzyme.
Purpose of the Study:
- To identify host factors regulating HCMV reproduction.
- To elucidate the mechanism by which HCMV subverts cellular mRNA metabolism.
Main Methods:
- Targeted loss-of-function screen in primary human fibroblasts.
- Nanopore direct RNA sequencing to profile poly(A)-tail lengths of viral and host mRNAs.
Main Results:
- CNOT1 and CNOT3 of the CCR4-NOT deadenylase complex were identified as pro-viral host factors.
- CNOT1 is essential for late viral gene expression and host responses in disrupted cells.
- Viral mRNAs have longer poly(A)-tails than host mRNAs and are less sensitive to CCR4-NOT disruption.
Conclusions:
- Host CCR4-NOT-mediated mRNA deadenylation is critical for productive HCMV replication.
- HCMV infection subverts cellular mRNA metabolism via a novel mechanism.
- CNOT1 and CNOT3 are potential therapeutic targets for anti-HCMV strategies.
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