Nuclear Export and Expression of Human T-Cell Leukemia Virus Type 1
            <i>tax</i>
            /
            <i>rex</i>
            mRNA Are RxRE/Rex Dependent

Bai, Xue; Sinha-Datta, Uma; Ko, Nga Ling; Bellon, Marcia; Nicot, Christophe

doi:10.1128/jvi.06361-11

Cited by 22 publications

(26 citation statements)

References 36 publications

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“…Why HIV-1 exploits the CRM1 pathway as opposed to the NXF1/NXT pathway that mediates the bulk of cellular mRNA nuclear export is unknown. However, Rev and Rev-equivalent proteins found in other retroviruses clearly provide a sophisticated feedback mechanism for tight regulation of late viral gene expression, with possible roles in viral persistence and immune evasion (11)(12)(13)(14). Moreover, Rev may govern the efficiency of downstream cytoplasmic events, including Gag/GagPol translation (15), gRNA packaging (16), and virus particle assembly occurring at the plasma membrane (17,18), through regulating the composition of distinct Rev/mRNA viral ribonucleoprotein (vRNP) complexes (19,20).…”

mentioning

confidence: 99%

Cooperativity among Rev-Associated Nuclear Export Signals Regulates HIV-1 Gene Expression and Is a Determinant of Virus Species Tropism

Aligeti

Behrens

Pocock

et al. 2014

J Virol

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Murine cells exhibit a profound block to HIV-1 virion production that was recently mapped to a species-specific structural attribute of the murine version of the chromosomal region maintenance 1 (mCRM1) nuclear export receptor and rescued by the expression of human CRM1 (hCRM1). In human cells, the HIV-1 Rev protein recruits hCRM1 to intron-containing viral mRNAs encoding the Rev response element (RRE), thereby facilitating viral late gene expression. Here we exploited murine 3T3 fibroblasts as a gain-of-function system to study hCRM1's species-specific role in regulating Rev's effector functions. We show that Rev is rapidly exported from the nucleus by mCRM1 despite only weak contributions to HIV-1's posttranscriptional stages. Indeed, Rev preferentially accumulates in the cytoplasm of murine 3T3 cells with or without hCRM1 expression, in contrast to human HeLa cells, where Rev exhibits striking en masse transitions between the nuclear and cytoplasmic compartments. Efforts to bias Rev's trafficking either into or out of the nucleus revealed that Rev encoding a second CRM1 binding domain (Rev-2xNES) or Rev-dependent viral gag-pol mRNAs bearing tandem RREs (GP-2xRRE), rescue virus particle production in murine cells even in the absence of hCRM1. Combined, these results suggest a model wherein Rev-associated nuclear export signals cooperate to regulate the number or quality of CRM1's interactions with viral Rev/RRE ribonucleoprotein complexes in the nucleus. This mechanism regulates CRM1-dependent viral gene expression and is a determinant of HIV-1's capacity to produce virions in nonhuman cell types. IMPORTANCECells derived from mice and other nonhuman species exhibit profound blocks to HIV-1 replication. Here we elucidate a block to HIV-1 gene expression attributable to the murine version of the CRM1 (mCRM1) nuclear export receptor. In human cells, hCRM1 regulates the nuclear export of viral intron-containing mRNAs through the activity of the viral Rev adapter protein that forms a multimeric complex on these mRNAs prior to recruiting hCRM1. We demonstrate that Rev-dependent gene expression is poor in murine cells despite the finding that, surprisingly, the bulk of Rev interacts efficiently with mCRM1 and is rapidly exported from the nucleus. Instead, we map the mCRM1 defect to the apparent inability of this factor to engage Rev multimers in the context of large viral Rev/RNA ribonucleoprotein complexes. These findings shed new light on HIV-1 gene regulation and could inform the development of novel antiviral strategies that target viral gene expression. T he nuclear pore complex (NPC) represents a key barrier to the replication of many viruses that infect eukaryotic cells (1-3). For retroviruses such as the primate lentivirus human immunodeficiency virus type 1 (HIV-1), the late, productive phases of the viral life cycle require efficient nuclear export of unspliced, and thus intron-containing, viral genomic RNAs (gRNAs) that (i) encode the group-specific antigen (Gag) and Gag-Pol polyproteins that form ...

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mentioning

confidence: 99%

Cooperativity among Rev-Associated Nuclear Export Signals Regulates HIV-1 Gene Expression and Is a Determinant of Virus Species Tropism

Aligeti

Behrens

Pocock

et al. 2014

J Virol

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Section: Discussionmentioning

confidence: 99%

“…However, studies based on expression of intronless mature mRNAs showed that expression of tax/rex, as well as other viral transcripts, may be enhanced by Rex through a canonical RXRE-and CRM1-dependent pathway (42,43). In fact, Rex is capable of binding tax/rex mRNA in chronically infected cell lines (43). The distinct observations made from a study of full-length proviruses versus mRNAs produced from cDNA expression plasmids indicate that the latter may be subjected to additional expression constraints that are not encountered by transcripts that interact with the splicing machinery.…”

Section: Discussionmentioning

confidence: 99%

Expression of Alternatively Spliced Human T-Cell Leukemia Virus Type 1 mRNAs Is Influenced by Mitosis and by a Novel cis -Acting Regulatory Sequence

Cavallari

Rende

Bona

et al. 2016

J Virol

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Human T-cell leukemia virus type 1 (HTLV-1) expression depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of viral expression. In the present study, we investigated the Rex dependence of the complete set of alternatively spliced HTLV-1 mRNAs. Analyses of cells transfected with Rex-wild-type and Rex-knockout HTLV-1 molecular clones using splice site-specific quantitative reverse transcription (qRT)-PCR revealed that mRNAs encoding the p30Tof, p13, and p12/8 proteins were Rex dependent, while the p21rex mRNA was Rex independent. These findings provide a rational explanation for the intermediate-late temporal pattern of expression of the p30tof, p13, and p12/8 mRNAs described in previous studies. All the Rex-dependent mRNAs contained a 75-nucleotide intronic region that increased the nuclear retention and degradation of a reporter mRNA in the absence of other viral sequences. Selective 2=-hydroxyl acylation analyzed by primer extension (SHAPE) analysis revealed that this sequence formed a stable hairpin structure. Cell cycle synchronization experiments indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. These findings indicate a link between the cycling properties of the host cell and the temporal pattern of viral expression/latency that might influence the ability of the virus to spread and evade the immune system. IMPORTANCEHTLV-1 is a complex retrovirus that causes two distinct pathologies termed adult T-cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-1-associated myelopathy in about 5% of infected individuals. Expression of the virus depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of virus expression. The findings reported in this study revealed a novel cisacting regulatory element and indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. Our results add a layer of complexity to the mechanisms controlling the expression of alternatively spliced HTLV-1 mRNAs and suggest a link between the cycling properties of the host cell and the temporal pattern of viral expression/ latency that might influence the ability of the virus to spread and evade the immune system. H uman T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia-lymphoma (ATLL) (1) and tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) (2). Accumulating evidence also supports an association between HTLV-1 infection and a number of chronic inflammatory diseases, including uveitis, arthropathy, and infective dermatitis (3).HTLV-1 produces many alternatively spliced transcripts coding for virion components and regulatory and accessory proteins ( Fig. 1) (4). The gag, pro, and pol genes are expre...

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“…p30 also regulates the cell cycle and the DNA damage response and is important for viral persistence in vivo (Anupam et al, 2013). ORF III encodes Rex which binds to the Rex response element on unspliced and singly spliced viral RNAs and shuttles these RNAs from the nucleus to the cytoplasm for translation by the host machinery (Bai et al, 2012). Tax is encoded by ORF IV and is essential for transactivation of viral gene expression by recruiting host transcription factors CREB and AP-1 and coactivators CBP/p300 to the LTR (Harrod et al, 1998).…”

Section: Human T-cell Leukemia Virus Type 1 (Htlv-1)mentioning

confidence: 99%

Functional implications of mitochondrial reactive oxygen species generated by oncogenic viruses

Choi

Harhaj²

2014

Front. Biol.

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Between 15–20% of human cancers are associated with infection by oncogenic viruses. Oncogenic viruses, including HPV, HBV, HCV and HTLV-1, target mitochondria to influence cell proliferation and survival. Oncogenic viral gene products also trigger the production of reactive oxygen species which can elicit oxidative DNA damage and potentiate oncogenic host signaling pathways. Viral oncogenes may also subvert mitochondria quality control mechanisms such as mitophagy and metabolic adaptation pathways to promote virus replication. Here, we will review recent progress on viral regulation of mitophagy and metabolic adaptation and their roles in viral oncogenesis.

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Nuclear Export and Expression of Human T-Cell Leukemia Virus Type 1 tax / rex mRNA Are RxRE/Rex Dependent

Cited by 22 publications

References 36 publications

Cooperativity among Rev-Associated Nuclear Export Signals Regulates HIV-1 Gene Expression and Is a Determinant of Virus Species Tropism

Cooperativity among Rev-Associated Nuclear Export Signals Regulates HIV-1 Gene Expression and Is a Determinant of Virus Species Tropism

Expression of Alternatively Spliced Human T-Cell Leukemia Virus Type 1 mRNAs Is Influenced by Mitosis and by a Novel cis -Acting Regulatory Sequence

Functional implications of mitochondrial reactive oxygen species generated by oncogenic viruses

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