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Genome-Wide Analysis of Heterogeneous Nuclear Ribonucleoprotein (hnRNP) Binding to HIV-1 RNA Reveals a Key Role for hnRNP H1 in Alternative Viral mRNA Splicing
- Source :
- Journal of virology. 93(21)
- Publication Year :
- 2019
-
Abstract
- Alternative splicing of HIV-1 mRNAs increases viral coding potential and controls the levels and timing of gene expression. HIV-1 splicing is regulated in part by heterogeneous nuclear ribonucleoproteins (hnRNPs) and their viral target sequences, which typically repress splicing when studied outside their native viral context. Here, we determined the location and extent of hnRNP binding to HIV-1 mRNAs and their impact on splicing in a native viral context. Notably, hnRNP A1, hnRNP A2, and hnRNP B1 bound to many dispersed sites across viral mRNAs. Conversely, hnRNP H1 bound to a few discrete purine-rich sequences, a finding that was mirrored in vitro. hnRNP H1 depletion and mutation of a prominent viral RNA hnRNP H1 binding site decreased the use of splice acceptor A1, causing a deficit in Vif expression and replicative fitness. This quantitative framework for determining the regulatory inputs governing alternative HIV-1 splicing revealed an unexpected splicing enhancer role for hnRNP H1 through binding to its target element. IMPORTANCE Alternative splicing of HIV-1 mRNAs is an essential yet quite poorly understood step of virus replication that enhances the coding potential of the viral genome and allows the temporal regulation of viral gene expression. Although HIV-1 constitutes an important model system for general studies of the regulation of alternative splicing, the inputs that determine the efficiency with which splice sites are utilized remain poorly defined. Our studies provide an experimental framework to study an essential step of HIV-1 replication more comprehensively and in much greater detail than was previously possible and reveal novel cis-acting elements regulating HIV-1 splicing.
- Subjects :
- Gene Expression Regulation, Viral
Heterogeneous nuclear ribonucleoprotein
Protein Conformation
viruses
Immunology
Context (language use)
Biology
Regulatory Sequences, Nucleic Acid
Heterogeneous ribonucleoprotein particle
Microbiology
03 medical and health sciences
0302 clinical medicine
Virology
Gene expression
RNA Precursors
vif Gene Products, Human Immunodeficiency Virus
Humans
RNA, Messenger
Enhancer
030304 developmental biology
0303 health sciences
Binding Sites
Heterogeneous-Nuclear Ribonucleoprotein Group F-H
Alternative splicing
Cell biology
Genome Replication and Regulation of Viral Gene Expression
Alternative Splicing
Viral replication
Insect Science
RNA splicing
HIV-1
RNA, Viral
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 10985514
- Volume :
- 93
- Issue :
- 21
- Database :
- OpenAIRE
- Journal :
- Journal of virology
- Accession number :
- edsair.doi.dedup.....93f93b02f5235aec557d9b5d51614281