Nucleocytoplasmic transport of HTLV-1 RNA is regulated by two independent LTR encoded nuclear retention elements

King, James G.; Bridger, Joanna M.; Löchelt, Martin; Lichter, Peter; Schulz, Thomas F.; Schirrmacher, Volker; Khazaie, Khashayarsha

doi:10.1038/sj.onc.1201884

Cited by 16 publications

(29 citation statements)

References 18 publications

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“…2A and B) and, as previously suggested (28), that the presence of the 3=-LTR sequence generates a posttranscriptional block that can be alleviated by Rex expression. Our results also suggest that a small fraction of tax/rex RNA can be expressed in the complete absence of Rex, since CMVtax/rex-3=LTR (RexϪ) still expressed a little of the Tax protein (Fig.…”

Section: Resultssupporting

confidence: 48%

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

Bai

Sinha-Datta

et al. 2012

J Virol

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Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus associated with the lymphoproliferative disease adult Tcell leukemia/lymphoma (ATL) and the neurodegenerative disorder tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). Replication of HTLV-1 is under the control of two major trans-acting proteins, Tax and Rex. Previous studies suggested that Tax activates transcription from the viral long terminal repeat (LTR) through recruitment of cellular CREB and transcriptional coactivators. Other studies reported that Rex acts posttranscriptionally and allows the cytoplasmic export of unspliced or incompletely spliced viral mRNAs carrying gag/pol and env only. As opposed to HIV's Rev-responsive element (RRE), the Rex-responsive element (RxRE) is present in all viral mRNAs in HTLV-1. However, based on indirect observations, it is believed that nuclear export and expression of the doubly spliced tax/rex RNA are Rex independent. In this study, we demonstrate that Rex does stimulate Tax expression, through nuclear-cytoplasmic export of the tax/rex RNA, even though a Rex-independent basal export mechanism exists. This effect was dependent upon the RxRE element and the RNA-binding activity of Rex. In addition, Rex-mediated export of tax/rex RNA was CRM1 dependent and inhibited by leptomycin B treatment. Like all other retroviruses, human T-cell leukemia virus type 1 (HTLV-1) has limited genetic information restricted by the small size of its genome. To overcome its small genome while reducing its dependency on the host cell machinery, HTLV-1 has evolved many strategies, including ribosome frameshifts, overlapping reading frames, complex alternative splicing patterns, reverse-sense RNA transcripts, and posttranslational processing/ modifications of viral proteins which ascribe distinct functions to them. Early observations of the existence of three major viral RNAs expressed in HTLV-1-infected cells, i.e., gag/pol, env, and tax/rex RNAs, led to the hypothesis that Rex positively regulates gag/pol and env RNAs while concomitantly reducing the abundance of the tax/rex RNA (25). Hence, HTLV-1 replication has been thought to be regulated by Tax and Rex proteins (14,27), though evidence suggests that additional viral proteins may also play an important role during the virus replication cycle (5, 32).Tax interaction with CREB family members and coactivators (CBP, P300, and PCAF) results in a high-molecular-weight complex with high affinity for binding to and transactivating the viral long terminal repeat (LTR) (15,23,26,30). Rex has at least three domains that are important for its functions: an arginine-rich region important for binding to the Rex-responsive element (RxRE) (8); a region required for multimerization of Rex, a step required for assembly onto the RxRE (6, 9); and a leucine-rich nuclear export signal that interacts with the nuclear export receptor, CRM1 (17,19). The ability of Rex to regulate expression of the gag and env structural genes posttranscriptionally is rigorously dependent o...

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Section: Resultssupporting

confidence: 48%

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

Bai

Sinha-Datta

et al. 2012

J Virol

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“…Indeed, Rex has been shown to bind pre-mRNA splicing factors such as SF2/ASF and inhibit mRNA splicing in vitro (42,99,100). In addition, studies by Seiki et al and King et al provide evidence that the RxRE acts as a negative element in the absence of Rex (101,102).…”

Section: The Rex Responsive Elementmentioning

confidence: 89%

The Human T-cell leukemia virus Rex protein

Ihab¹

2005

Front Biosci

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A critical step in the life cycle of complex retroviruses, including HTLV-1 and HTLV-2 is the ability of these viruses to adopt a mechanism by which the genome-length unspliced mRNA as well as the partially spliced mRNAs are exported from the nucleus instead of being subjected to splicing or degradation. In HTLV, this is accomplished through the expression of the viral Rex, which recognizes a specific response element on the incompletely spliced mRNAs, stabilizes them, inhibits their splicing, and utilizes the CRM1-dependent cellular pathway for transporting them from the nucleus to the cytoplasm. Rex itself is regulated by phosphorylation, which implies that proper activation of the protein in response to certain cellular cues is an important tool for the virus to ensure that specific viral gene expression is allowed only when the host cell can provide the best conditions for virion production. Having such a critical role in HTLV life cycle, Rex is indispensable for efficient viral replication, infection and spread. Indeed, Rex is considered to regulate the switch between the latent and productive phases of the HTLV life cycle. Without a functional Rex, the virus would still produce regulatory and some accessory gene products; however, structural and enzymatic post-transcriptional gene expression would be severely repressed, essentially leading to non-productive viral replication. More detailed understanding of the exact molecular mechanism of action of Rex will thus allow for better design of therapeutic drugs against Rex function and ultimately HTLV replication. Herein we summarize the progress made towards understanding Rex function and its role in the HTLV life cycle.

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“…In the absence of Rex, unspliced and incompletely spliced viral RNAs are retained in the nucleus and either completely spliced or degraded. Rex relieves constraints on the export of viral transcripts conferred by cis-acting negative elements identi®ed in the 5' and 3' LTRs (Black et al, 1991(Black et al, , 1994GroÈ ne et al, 1996;King et al, 1998). In addition, Rex appears to be a direct inhibitor of splicing (Bakker et al, 1996;GroÈ ne et al, 1996) and may therefore contribute to the oncogenic potential of HTLV-1 (Kanamori et al, 1990;McGuire et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Titration of cellular export factors, but not heteromultimerization, is the molecular mechanism of trans-dominant HTLV-1 Rex mutants

et al. 1999

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The HTLV-1 Rex protein is an essential shuttle protein required for nuclear export of unspliced and incompletely-spliced viral RNAs. Several trans-dominant (TD) mutant Rex proteins have been reported, however, the mechanism of trans-dominance is not known. We compared TD Rex mutants and found that a natural occurring Rex mutant, Rexp21, lacking the RNA binding domain, was highly TD and inhibited also HIV-1 Rev function. Using fusions to the green uorescent protein (GFP) we observed that Rexp21-GFP displayed a cytoplasmic localization but was actively shuttling between the nucleus and the cytoplasm in live human cells.

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Nucleocytoplasmic transport of HTLV-1 RNA is regulated by two independent LTR encoded nuclear retention elements

Cited by 16 publications

References 18 publications

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

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

The Human T-cell leukemia virus Rex protein

Titration of cellular export factors, but not heteromultimerization, is the molecular mechanism of trans-dominant HTLV-1 Rex mutants

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