Cleavage and Polyadenylation Specificity Factor 6 Is Required for Efficient HIV-1 Latency Reversal

CPSF6 is a cellular factor that regulates cleavage and polyadenylation of mRNAs and participates in HIV-1 infection by facilitating targeting of preintegration complexes to the chromatin. Our observations reveal a second role of CPSF6 in the HIV-1 life cycle that involves regulation of viral transcription through controlling the stability of protein phosphatase 2A, which in turn regulates the phosphorylation/dephosphorylation status of critical residues in CDK9 and Pol II.

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Structure, Function, and Interactions of the HIV-1 Capsid Protein

Life ◽

10.3390/life11020100 ◽

2021 ◽

Vol 11 (2) ◽

pp. 100

Author(s):

Eric Rossi ◽

Megan E. Meuser ◽

Camille J. Cunanan ◽

Simon Cocklin

Keyword(s):

Life Cycle ◽

Capsid Protein ◽

Adaptor Proteins ◽

Restriction Factors ◽

Gag Polyprotein ◽

Immunodeficiency Virus ◽

Host Cell Factors ◽

Hiv 1

The capsid (CA) protein of the human immunodeficiency virus type 1 (HIV-1) is an essential structural component of a virion and facilitates many crucial life cycle steps through interactions with host cell factors. Capsid shields the reverse transcription complex from restriction factors while it enables trafficking to the nucleus by hijacking various adaptor proteins, such as FEZ1 and BICD2. In addition, the capsid facilitates the import and localization of the viral complex in the nucleus through interaction with NUP153, NUP358, TNPO3, and CPSF-6. In the later stages of the HIV-1 life cycle, CA plays an essential role in the maturation step as a constituent of the Gag polyprotein. In the final phase of maturation, Gag is cleaved, and CA is released, allowing for the assembly of CA into a fullerene cone, known as the capsid core. The fullerene cone consists of ~250 CA hexamers and 12 CA pentamers and encloses the viral genome and other essential viral proteins for the next round of infection. As research continues to elucidate the role of CA in the HIV-1 life cycle and the importance of the capsid protein becomes more apparent, CA displays potential as a therapeutic target for the development of HIV-1 inhibitors.

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Role of Vif in Stability of the Human Immunodeficiency Virus Type 1 Core

Journal of Virology ◽

10.1128/jvi.74.23.11055-11066.2000 ◽

2000 ◽

Vol 74 (23) ◽

pp. 11055-11066 ◽

Cited By ~ 53

Author(s):

Åsa Öhagen ◽

Dana Gabuzda

Keyword(s):

Human Immunodeficiency Virus ◽

Dna Synthesis ◽

Virus Entry ◽

Wild Type ◽

The Core ◽

Immunodeficiency Virus ◽

The Stability ◽

Hiv 1

ABSTRACT The Vif protein of human immunodeficiency virus type 1 (HIV-1) is important for virion infectivity. Previous studies have shown thatvif-defective virions exhibit structural abnormalities in the virus core and are defective in the ability to complete proviral DNA synthesis in acutely infected cells. We developed novel assays to assess the relative stability of the core in HIV-1 virions. Using these assays, we examined the role of Vif in the stability of the HIV-1 core. The integrity of the core was examined following virion permeabilization or removal of the lipid envelope and treatment with various triggers, including S100 cytosol, deoxynucleoside triphosphates, detergents, NaCl, and buffers of different pH to mimic aspects of the uncoating and disassembly process which occurs after virus entry but preceding or during reverse transcription.vif mutant cores were more sensitive to disruption by all triggers tested than wild-type cores, as determined by endogenous reverse transcriptase (RT) assays, biochemical analyses, and electron microscopy. RT and the p7 nucleocapsid protein were released more readily from vif mutant virions than from wild-type virions, suggesting that the internal nucleocapsid is less stably packaged in the absence of Vif. Purified cores could be isolated from wild-type but not vif mutant virions by sedimentation through detergent-treated gradients. These results demonstrate that Vif increases the stability of virion cores. This may permit efficient viral DNA synthesis by preventing premature degradation or disassembly of viral nucleoprotein complexes during early events after virus entry.

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Going beyond Integration: The Emerging Role of HIV-1 Integrase in Virion Morphogenesis

Viruses ◽

10.3390/v12091005 ◽

2020 ◽

Vol 12 (9) ◽

pp. 1005 ◽

Cited By ~ 2

Author(s):

Jennifer L. Elliott ◽

Sebla B. Kutluay

Keyword(s):

Life Cycle ◽

Viral Genome ◽

Critical Role ◽

Viral Rna ◽

Target Cells ◽

Host Chromosome ◽

Virion Morphogenesis ◽

Rna Genome ◽

Hiv 1

The HIV-1 integrase enzyme (IN) plays a critical role in the viral life cycle by integrating the reverse-transcribed viral DNA into the host chromosome. This function of IN has been well studied, and the knowledge gained has informed the design of small molecule inhibitors that now form key components of antiretroviral therapy regimens. Recent discoveries unveiled that IN has an under-studied yet equally vital second function in human immunodeficiency virus type 1 (HIV-1) replication. This involves IN binding to the viral RNA genome in virions, which is necessary for proper virion maturation and morphogenesis. Inhibition of IN binding to the viral RNA genome results in mislocalization of the viral genome inside the virus particle, and its premature exposure and degradation in target cells. The roles of IN in integration and virion morphogenesis share a number of common elements, including interaction with viral nucleic acids and assembly of higher-order IN multimers. Herein we describe these two functions of IN within the context of the HIV-1 life cycle, how IN binding to the viral genome is coordinated by the major structural protein, Gag, and discuss the value of targeting the second role of IN in virion morphogenesis.

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2214 Role of protein phosphatase 2A in hippocampal long-term potentiation

Neuroscience Research ◽

10.1016/s0168-0102(97)90699-4 ◽

1997 ◽

Vol 28 ◽

pp. S254

Author(s):

Kohji Fukunaga ◽

Dominique Muller ◽

Masao Ohmitsu ◽

Eishichi Miyamoto

Keyword(s):

Protein Phosphatase ◽

Protein Phosphatase 2A ◽

Long Term Potentiation ◽

Term Potentiation ◽

Phosphatase 2A

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Role of Protein Phosphatase 2A in Regulating the Visual Signaling in Drosophila

Journal of Neuroscience ◽

10.1523/jneurosci.5134-07.2008 ◽

2008 ◽

Vol 28 (6) ◽

pp. 1444-1451 ◽

Cited By ~ 11

Author(s):

N. Wang ◽

H.-T. Leung ◽

W. L. Pak ◽

Y. T. Carl ◽

B. E. Wadzinski ◽

...

Keyword(s):

Protein Phosphatase ◽

Protein Phosphatase 2A ◽

Visual Signaling ◽

Phosphatase 2A

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The HIV-1 capsid-binding host factor CPSF6 is post-transcriptionally regulated by the cellular microRNA miR-125b

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.010534 ◽

2020 ◽

Vol 295 (15) ◽

pp. 5081-5094

Author(s):

Evan Chaudhuri ◽

Sabyasachi Dash ◽

Muthukumar Balasubramaniam ◽

Adrian Padron ◽

Joseph Holland ◽

...

Keyword(s):

Molecular Mechanisms ◽

Mammalian Species ◽

Cellular Protein ◽

Luciferase Reporter ◽

Down Regulation ◽

Host Interaction ◽

Cleavage And Polyadenylation ◽

Specificity Factor ◽

Viral Dna Integration ◽

Hiv 1

Cleavage and polyadenylation specificity factor 6 (CPSF6) is a cellular protein involved in mRNA processing. Emerging evidence suggests that CPSF6 also plays key roles in HIV-1 infection, specifically during nuclear import and integration targeting. However, the cellular and molecular mechanisms that regulate CPSF6 expression are largely unknown. In this study, we report a post-transcriptional mechanism that regulates CPSF6 via the cellular microRNA miR-125b. An in silico analysis revealed that the 3′UTR of CPSF6 contains a miR-125b–binding site that is conserved across several mammalian species. Because miRNAs repress protein expression, we tested the effects of miR-125b expression on CPSF6 levels in miR-125b knockdown and over-expression experiments, revealing that miR-125b and CPSF6 levels are inversely correlated. To determine whether miR-125b post-transcriptionally regulates CPSF6, we introduced the 3′UTR of CPSF6 mRNA into a luciferase reporter and found that miR-125b negatively regulates CPSF6 3′UTR-driven luciferase activity. Accordingly, mutations in the miR-125b seed sequence abrogated the regulatory effect of the miRNA on the CPSF6 3′UTR. Finally, pulldown experiments demonstrated that miR-125b physically interacts with CPSF6 3′UTR. Interestingly, HIV-1 infection down-regulated miR-125b expression concurrent with up-regulation of CPSF6. Notably, miR-125b down-regulation in infected cells was not due to reduced pri-miRNA or pre-miRNA levels. However, miR-125b down-regulation depended on HIV-1 reverse transcription but not viral DNA integration. These findings establish a post-transcriptional mechanism that controls CPSF6 expression and highlight a novel function of miR-125b during HIV-host interaction.

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A New Role of Protein Phosphatase 2A in Adenoviral E1A Protein-Mediated Sensitization to Anticancer Drug-Induced Apoptosis in Human Breast Cancer Cells

Cancer Research ◽

10.1158/0008-5472.can-04-1533 ◽

2004 ◽

Vol 64 (17) ◽

pp. 5938-5942 ◽

Cited By ~ 39

Author(s):

Yong Liao ◽

Mien-Chie Hung

Keyword(s):

Breast Cancer ◽

Protein Phosphatase ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Drug Induced ◽

Phosphatase 2A ◽

Induced Apoptosis

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The Role of RNA Polymerase II Elongation Control in HIV-1 Gene Expression, Replication, and Latency

Genetics Research International ◽

10.4061/2011/726901 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Kyle A. Nilson ◽

David H. Price

Keyword(s):

Rna Polymerase ◽

Rna Polymerase Ii ◽

Elongation Factor ◽

Health Concern ◽

Pol Ii ◽

Positive Transcription Elongation Factor ◽

Elongation Control ◽

Hiv 1 ◽

Latent Phase

HIV-1 usurps the RNA polymerase II elongation control machinery to regulate the expression of its genome during lytic and latent viral stages. After integration into the host genome, the HIV promoter within the long terminal repeat (LTR) is subject to potent downregulation in a postinitiation step of transcription. Once produced, the viral protein Tat commandeers the positive transcription elongation factor, P-TEFb, and brings it to the engaged RNA polymerase II (Pol II), leading to the production of viral proteins and genomic RNA. HIV can also enter a latent phase during which factors that regulate Pol II elongation may play a role in keeping the virus silent. HIV, the causative agent of AIDS, is a worldwide health concern. It is hoped that knowledge of the mechanisms regulating the expression of the HIV genome will lead to treatments and ultimately a cure.

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