A human nucleoporin-like protein that specifically interacts with HIV Rev

Fritz, Christian; Zapp, Maria L.; Green, Michael R.

doi:10.1038/376530a0

Cited by 248 publications

(222 citation statements)

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“…This is consistent with our earlier results which demonstrated that the human immunode®ency type 1 (HIV-1) Rev/RRE regulatory axis could overcome the inhibitory e ect of the h1ARE . The HIV-1 Rev protein binds to its target RNA element in the nucleus and acts by promoting export of nuclear mRNAs (Emerman et al, 1989;Felber et al, 1989;HammarskjoÈ ld et al, 1989;Malim et al, 1989) through an alternative, productive route (Bogerd et al, 1995;Fisher et al, 1995;Fritz et al, 1995), thereby presumably preventing the h1ARE from interacting with nuclear proteins that mediate inhibition as the mRNA enters the cytoplasm. Recent reports have described the identi®cation of an RNaseE like activity in mammalian cells and have shown that partially puri®ed mammalian RNaseE cleaves AUUUA containing RNAs in vitro (Wennborg et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

AU-rich mRNA instability elements on human papillomavirus type 1 late mRNAs and c-fos mRNAs interact with the same cellular factors

et al. 1997

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Expression levels of human papillomavirus type 1 late genes are determined in part by an AU-rich inhibitory sequence in the 3' untranslated region on the late mRNAs. Fine mapping of the AU rich inhibitory sequence revealed that it mapped to a 57 nucleotide sequence, consisting of an AU-rich region containing two AUUUA motifs and a U-rich region containing three UUUUU motifs. An internal deletion showed that the Urich region was required for inhibition. Point mutations in the AUUUA-and UUUUU-motifs inactivated the inhibitory sequence. Analysis of the stability of mRNAs containing the AU-rich sequence in sense or anti-sense orientation showed that mRNAs containing the AU-rich sequence in sense orientation had reduced half life. Analysis of RNA-protein interactions revealed that binding to the inhibitory sequence of three poly(U) binding proteins (38, 44 and 46 kDa) correlated with inhibition and that the same proteins bind to the AU-rich mRNA instability element in the 3' untranslated region on the human c-fos mRNA. We speculate that the human papillomavirus late mRNAs, produced from several hundred copies of the virus genome present in infected cells, compete with the c-fos mRNAs for destabilizing cellular factors and that this may lead to elevated Fos protein levels in human papillomavirus infected cells

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Section: Discussionmentioning

confidence: 99%

AU-rich mRNA instability elements on human papillomavirus type 1 late mRNAs and c-fos mRNAs interact with the same cellular factors

et al. 1997

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“…Additional effects of Rev are likely to occur at the level of facilitating viral RNA transport or translation. These transport effects could involve the specific interplay of other cellular factors, such as the nucleoporin-like Rab͞Rip proteins (49)(50)(51) or eIF 5A (52,53), with the leucine-rich activation domain of Rev (7), which functions as a nuclear export signal (54,55). Mutation of this leucine-rich domain results in the formation of potent dominant-negative inhibitors of Rev (56), which already have shown promise in early clinical trials (57).…”

Section: Discussionmentioning

confidence: 99%

HIV Rev-dependent binding of SF2/ASF to the Rev response element: Possible role in Rev-mediated inhibition of HIV RNA splicing

Powell

Amaral

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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Production of the structural and enzymatic proteins of type 1 human immunodeficiency virus (HIV-1) is controlled by the rev regulatory gene product. The 116-amino acid Rev protein acts by binding to the Rev response element (RRE), a complex RNA stem-loop structure located within the env gene of HIV. Rev exerts a series of posttranscriptional effects, including the inhibition of viral RNA splicing, the activation of nuclear export of incompletely spliced viral RNAs, and the enhancement of translation of RRE-containing RNAs. Our studies now demonstrate that at least one member of the SR family of splicing factors, SF2͞ASF, specifically binds to a subregion of the RRE in vitro in a Rev-dependent manner. Furthermore, expression of high levels of SF2͞ASF inhibits Rev function and impairs HIV replication in vivo. Both the in vitro binding of SF2͞ASF to the Rev͞RRE complex and the in vivo inhibition of Rev action by SF2͞ASF are abrogated by mutation of the N-terminal RNA recognition motif but are not affected by mutation of the C-terminal arginine-serinerich domain. These findings suggest that Rev inhibition of HIV splicing likely involves recruitment of the essential splicing factor SF2͞ASF to the Rev͞RRE complex. However, these inhibitory effects of Rev on viral RNA splicing are apparently overcome by augmenting the intracellular levels of SF2͞ASF expression.Rev is an essential regulatory protein of the type 1 human immunodeficiency virus (HIV-1) that controls production of proteins required for the assembly of infectious virions (1-5). The 9-kb full-length genomic transcript of HIV undergoes a complex series of posttranscriptional splicing events resulting in the generation of more than 20 mRNAs that encode 9 different viral proteins (for review see refs. 6-8). The resultant mRNAs can be grouped in three size classes: the 2-kb viral RNAs are fully spliced and encode the regulatory proteins of HIV, including Rev, Tat, and Nef, whereas the 9-and 4-kb mRNAs encode the structural, enzymatic, and ancillary viral proteins, including Gag, Pol, Vif, Vpu, Vpr, and Env. The appearance of the 4-and 9-kb classes of mRNAs in the cytoplasm is regulated by the Rev protein (1-5). Rev binds specifically to the Rev response element (RRE), a complex 220-nucleotide RNA stem-loop structure located in the env coding sequence. This binding leads to effective cytoplasmic expression of the singly spliced (4 kb) and unspliced (9 kb) viral mRNAs, thus allowing the transition from early-stage regulatory protein synthesis to late-stage structural and enzymatic viral protein production (2, 6, 7). In the absence of Rev, these incompletely spliced RRE-containing transcripts are retained in the nucleus where they are either completely spliced or degraded (6, 7). Various mechanisms have been suggested to explain the action of Rev, including inhibition of viral mRNA splicing, activation of viral RNA transport from the nucleus to the cytoplasm, and enhanced translation of RRE-containing viral RNAs (1, 6-8). These mechanisms are not mutually ex...

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“…The yeast Riplp (Stutz et al, 1995) and the mammalian Rab/hRIPl (Bogerd et al, 1995;Fritz et al, 1995) are candidates for a NES receptor that were isolated in independent two-hybrid screens. These proteins contain multiple FG amino acid repeats typical of NPC proteins (nucleoporins; Rout and Wente, 1994).…”

Section: Introductionmentioning

confidence: 99%

GLE2, a Saccharomyces cerevisiae homologue of the Schizosaccharomyces pombe export factor RAE1, is required for nuclear pore complex structure and function.

Murphy

Watkins

Wente

1996

MBoC

168

164

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To identify and characterize novel factors required for nuclear transport, a genetic screen was conducted in the yeast Saccharomyces cerevisiae. Mutations that were lethal in combination with a null allele of the gene encoding the nucleoporin NuplOOp were isolated using a colony-sectoring assay. Three complementation groups of gle (for GLFG lethal) mutants were identified. In this report, the characterization of GLE2 is detailed. GLE2 encodes a 40.5-kDa polypeptide with striking similarity to that of Schizosaccharomyces pombe RAE1. In indirect immunofluorescence and nuclear pore complex fractionation experiments, Gle2p was associated with nuclear pore complexes. Mutated alleles of GLE2 displayed blockage of polyadenylated RNA export; however, nuclear protein import was not apparently diminished. Immunofluorescence and thin-section electron microscopic analysis revealed that the nuclear pore complex and nuclear envelope structure was grossly perturbed in gle2 mutants. Because the clusters of herniated pore complexes appeared subsequent to the export block, the structural perturbations were likely indirect consequences of the export phenotype. Interestingly, a two-hybrid interaction was detected between Gle2p and Srplp, the nuclear localization signal receptor, as well as Riplp, a nuclear export signal-interacting protein. We propose that Gle2p has a novel role in mediating nuclear transport.

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A human nucleoporin-like protein that specifically interacts with HIV Rev

Cited by 248 publications

References 19 publications

AU-rich mRNA instability elements on human papillomavirus type 1 late mRNAs and c-fos mRNAs interact with the same cellular factors

AU-rich mRNA instability elements on human papillomavirus type 1 late mRNAs and c-fos mRNAs interact with the same cellular factors

HIV Rev-dependent binding of SF2/ASF to the Rev response element: Possible role in Rev-mediated inhibition of HIV RNA splicing

GLE2, a Saccharomyces cerevisiae homologue of the Schizosaccharomyces pombe export factor RAE1, is required for nuclear pore complex structure and function.

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