The HIV-1 Rev Activation Domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs

Fischer, Utz; Huber, J.; Boelens, Wilbert C.; Mattaj, Iain W.; Lührmann, Reinhard

doi:10.1016/0092-8674(95)90436-0

Cited by 1,071 publications

(1,041 citation statements)

References 38 publications

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“…One, not yet shown directly but inferred from studies m the HIV equivalent Rev [15,16], is that Rex promotes ex~ort of viral RNAs by binding to the RexRE on the RNA md dragging the RNA out of the nucleus. In this respect a ~uclear export signal has been identified on Rex [13]. The ~econd activity would involve the ability of Rex to stabilise ~he incompletely spliced viral transcripts, containing one or wo introns, so that detectable levels are present in the nucleus -in the absence of Rex these transcripts are almost absent [5].…”

Section: Discussionmentioning

confidence: 99%

“…FITC, fluorescein isothiocyanate; HIV, human immunodeficiency virus; HTLV-1, human T-cell leukaemic virus type 1 ; NOS, nucleolar localisation signal; RexRE, Rex-responsive element merisation [11] and for binding to the responsive element on the viral RNA [8,12]. A C-terminal domain encodes a leucinerich effector domain which includes a recently characterised nuclear export signal [13,14]. The combination of nuclear import and export signals accounts for the demonstrated ability of Rev to shuttle between the nucleus and cytoplasm [15,16].…”

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confidence: 99%

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Enhancement of nucleocytoplasmic export of HTLV‐1 Rex mRNA through cis and trans interactions of the mRNA with the complex of Rex protein and Rex‐responsive element

White

1996

FEBS Letters

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p27 rex of HTLV-1 promotes nucleocytoplasmic t xport of viral mRNAs through binding of the Rex-response element (RexRE) present at the 3' end of the viral transcripts in ds with respect to the ORFs of the viral mRNAs. We have found that expression of the RexRE in trans, as a separate RNA, still allows Rex protein to promote export of viral mRNAs lacking the RexRE. The data suggest the formation of a ternary complex between Rex protein, RexRE and upstream elements of viral mRNA and hence the existence of secondary sites of interaction between Rex protein and viral RNAs.~ey words: mRNA export; HTLV-1; Retrovirus; p27rex; t,'~ex-responsive element; Fluorescence in situ hybridisation !. IntroductionHuman T-cell leukaemic virus type 1 (HTLV-1) is a retro-, irus trophic for CD4 + T-cells associated with an aggressive lorm of leukaemia, adult T-cell leukaemia [1,2], and with a ~eurological disorder, tropical spastic paraparesis, also due to infection of T-cells [3]. In order to co-ordinate the regulation ,,f the structural and viral proteins necessary for viral replication a nuclear protein, Rex, encoded in the viral genome, makes efficient use of variably spliced reading frames in the , iral genome (reviewed in [4]). In the presence of Rex incom-1,1etely spliced transcripts of viral RNA are expressed in the • ytoplasm, allowing expression of proteins from the unspliced :ag-pol transcript and the singly spliced env transcript. In the ,,bsence of Rex the incompletely spliced transcripts remain .equestered in the nucleus to be degraded or for completion ,,f splicing [5,6]. Completely spliced transcripts encode the ~egulatory proteins of the virus, Tax and Rex [5]. Rex works i~y binding directly to a highly structured element of RNA of ~kbout 250 bases present in the viral transcripts, the Rex-re-, ponsive element (RexRE) [7][8][9]. Details of the mechanism of ~tction of Rex, and its analogue Rev from human immunode-!tciency virus (HIV) type 1, are becoming apparent. Despite ~heir lack of sequence homology both proteins contain two orresponding functional domains. The N-terminal domain is ~ich in basic amino acid residues and serves as a nuclear i ocalisation signal, which also has nucleolar localising capabilty [10]. In addition the same domain is the site for multi-' Corresponding author. Fax: (44) (171) 955-4191. E-mail: k.white@umds.ac.ukIbbreviations. FITC, fluorescein isothiocyanate; HIV, human immunodeficiency virus; HTLV-1, human T-cell leukaemic virus type 1 ; NOS, nucleolar localisation signal; RexRE, Rex-responsive element merisation [11] and for binding to the responsive element on the viral RNA [8,12]. A C-terminal domain encodes a leucinerich effector domain which includes a recently characterised nuclear export signal [13,14]. The combination of nuclear import and export signals accounts for the demonstrated ability of Rev to shuttle between the nucleus and cytoplasm [15,16].Two models have been proposed to account for the retention of unspliced viral mRNAs in the nucleus and for the relief of the ...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Enhancement of nucleocytoplasmic export of HTLV‐1 Rex mRNA through cis and trans interactions of the mRNA with the complex of Rex protein and Rex‐responsive element

White

1996

FEBS Letters

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“…The most extensively studied and most commonly utilized protein export pathway is mediated by the chromosome region maintenance 1 (CRM1) protein [34,35]. This export receptor protein recognizes short, leucine-rich amino acid stretches termed nuclear export sequences (NESs) similar to that present in the HIV-1 Rev protein [36]. The ability of CRM1 to function as an export receptor can be inhibited by the metabolite leptomycin B (LMB) [34].…”

Section: Eklf Can Shuttle Between Nuclei In Heterokaryonsmentioning

confidence: 99%

Non-random subcellular distribution of variant EKLF in erythroid cells

Quadrini¹,

Gruzglin²,

Bieker³

2008

Experimental Cell Research

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EKLF protein plays a prominent role during erythroid development as a nuclear transcription factor. Not surprisingly, exogenous EKLF quickly localizes to the nucleus. However, using two different assays we have unexpectedly found that a substantial proportion of endogenous EKLF resides in the cytoplasm at steady state in all erythroid cells examined. While EKLF localization does not appear to change during either erythroid development or terminal differentiation, we find that the protein displays subtle yet distinct biochemical and functional differences depending on which subcellular compartment it is isolated from, with PEST sequences possibly playing a role in these differences. Localization is unaffected by inhibition of CRM1 activity and the two populations are not differentiated by stability. Heterokaryon assays demonstrate that EKLF is able to shuttle out of the nucleus although its nuclear re-entry is rapid. These studies suggest there is an unexplored role for EKLF in the cytoplasm that is separate from its well-characterized nuclear function.

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“…According to present knowledge the latter pathway seems to be more likely since a partial capture would require an unknown factor competing with the importins for Vigilin. Although specific nuclear export signals have been recently identified in a few proteins [27][28][29], there is also evidence arguing for nuclear export by a default pathway [30,31]. At present experimental evidence is lacking which could show whether Vigilin shuttles continuously across the nuclear envelope like some nucleolar proteins [32], the progesterone receptor [33] or some of the hnRNPs [27], or is stably anchored at the ER after it had passed by the nucleus.…”

Section: Vigilin Is Present Both In the Cytoplasm And In The Nucleusmentioning

confidence: 99%

Vigilin contains a functional nuclear localisation sequence and is present in both the cytoplasm and the nucleus

et al. 1996

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Vigilin is a member of the KH protein family and contains 14 tandemly arranged potential RNA-binding domains. Between KH domains 2 and 3 we have identified a nuclear localization sequence by cloning this sequence into the NH2-terminal region of phage T7 RNA polymerase as a reporter protein and by showing its transfer into the nucleus. Furthermore we provide experimental evidence that Vigilin is present both in the nucleus and in the cytoplasm in similar concentrations. These observations support the notion that Vigilin may shuttle between nucleus and cytoplasm presumably in contact with RNA molecules.

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The HIV-1 Rev Activation Domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs

Cited by 1,071 publications

References 38 publications

Enhancement of nucleocytoplasmic export of HTLV‐1 Rex mRNA through cis and trans interactions of the mRNA with the complex of Rex protein and Rex‐responsive element

Enhancement of nucleocytoplasmic export of HTLV‐1 Rex mRNA through cis and trans interactions of the mRNA with the complex of Rex protein and Rex‐responsive element

Non-random subcellular distribution of variant EKLF in erythroid cells

Vigilin contains a functional nuclear localisation sequence and is present in both the cytoplasm and the nucleus

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