Rev is necessary for translation but not cytoplasmic accumulation of HIV-1 vif, vpr, and env/vpu 2 RNAs.

Arrigo, Salvatore J.; Chen, I. S. Y.

doi:10.1101/gad.5.5.808

Cited by 224 publications

(176 citation statements)

References 37 publications

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“…First, Rev is required for efficient translation of the introncontaining gag-pol and env RNAs (Arrigo and Chen 1991;Lawrence et al 1991;D'Agostino et al 1992;Favaro et al 1999) and has been proposed to direct viral RNAs to the translation machinery (Kimura et al 1996;Coyle et al 2003). Second, the cellular protein SAM68 (src-associated in mitosis) can partially substitute for Rev in transient transfection assays (Reddy et al 1999;Soros et al 2001).…”

Section: An Extended Role For Revmentioning

confidence: 99%

hRIP, a cellular cofactor for Rev function, promotes release of HIV RNAs from the perinuclear region

Sánchez-Velar

Udofia²,

Yu³

et al. 2003

Genes Dev.

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Human immunodeficiency virus Rev facilitates the cytoplasmic accumulation of viral RNAs that contain aRev binding site. A human Rev-interacting protein (hRIP) was originally identified based on its ability to interact with the Rev nuclear export signal (NES) in yeast two-hybrid assays. To date, however, the function of hRIP and a role for hRIP in Rev-directed RNA export have remained elusive. Here we ablate hRIP activity with a dominant-negative mutant or RNA interference and analyze Rev function by RNA in situ hybridization. We find, unexpectedly, that in the absence of functional hRIP, Rev-directed RNAs mislocalize and aberrantly accumulate at the nuclear periphery, where hRIP is localized. In contrast, in the absence of Rev or the Rev cofactor CRM1, Rev-directed RNAs remain nuclear. We further show that the RNA mislocalization pattern resulting from loss of hRIP activity is highly specific to Rev function: the intracellular distribution of cellular poly(A) + mRNA, nuclear proteins, and, most important, NES-containing proteins, are unaffected. Thus, hRIP is an essential cellular Rev cofactor, which acts at a previously unanticipated step in HIV-1 RNA export: movement of RNAs from the nuclear periphery to the cytoplasm. Animal viruses often encode regulatory proteins, which facilitate expression of their viral genes in the host cell. One such example is the human immunodeficiency virus type 1 (HIV-1) Rev protein, which uses a novel mechanism to regulate viral messenger RNA (mRNA) export from the nucleus. Rev is a sequence-specific RNA binding protein that facilitates the cytoplasmic accumulation of the intron-containing HIV-1 gag-pol and env mRNAs (Cullen 2002). Rev interacts with a cis-acting viral RNA element in these mRNAs designated the Rev responsive element (RRE; Pollard and Malim 1998; Hope 1999). Rev contains two distinct functional domains: an arginine-rich RNA binding motif (ARM) and a leucinerich "effector" domain. Rev's ARM domain confers sequence-specific RNA binding, protein oligomerization, and nuclear targeting (Frankel and Young 1998). Rev's effector domain contains a leucine-rich nuclear export signal (NES), which binds the nuclear export receptor CRM1 (Weis 2002). Other cellular proteins have been shown to interact directly or indirectly with the Rev NES, including the kinesin-like Rev/Rex effector binding protein (REBP) and the eukaryotic initiation factor-5 alpha (eIF-5␣; Bevec et al. 1996;Dayton 1996;Kjems and Askjaer 2000;Venkatesh et al. 2003).The human Rev-interacting protein (hRIP), also known as hRab or Hrb, was identified using a yeast twohybrid screen with Rev as the bait (Bogerd et al. 1995;Fritz et al. 1995). Additional studies demonstrated a strong correlation between the ability of Rev NES mutants to support Rev function in yeast and their ability to interact with hRIP in the two-hybrid assay (Stutz et al. 1996). However, subsequent genetic analyses indicate the Rev-hRIP interaction is indirect, and is likely bridged by CRM1 (Fritz and Green 1996;Henderson and Percipalle 1997;Ne...

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Section: An Extended Role For Revmentioning

confidence: 99%

hRIP, a cellular cofactor for Rev function, promotes release of HIV RNAs from the perinuclear region

Sánchez-Velar

Udofia²,

Yu³

et al. 2003

Genes Dev.

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“…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)(7)(8). These mechanisms are not mutually exclusive, and Rev may exert effects at multiple levels.…”

mentioning

confidence: 99%

“…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)(2)(3)(4)(5). Rev binds specifically to the Rev response element (RRE), a complex 220-nucleotide RNA stem-loop structure located in the env coding sequence.…”

mentioning

confidence: 99%

“…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)(2)(3)(4)(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.…”

mentioning

confidence: 99%

“…These viral RNAs contain cis-acting elements termed cis-repressor sequences or inhibitory sequences, which may be responsible for instability, nuclear retention, and͞or inefficient translation (1,2,7,9). Rev appears to overcome the effects of these cis-repressor͞inhibitory sequence elements.…”

mentioning

confidence: 99%

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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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Evidence that HIV-1 Rev directly promotes the nuclear export of unspliced RNA.

Fischer¹,

Meyer²,

Teufel³

et al. 1994

The EMBO Journal

239

182

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The Rev trans-activator of human immunodeficiency virus type 1 (HIV-1) is a protein that regulates the simultaneous appearance in the cytoplasm of both spliced and unspliced forms of viral mRNAs from the same viral transcripts by way of recognition of a target sequence termed the Rev-responsive element (RRE). Whether Rev acts directly on RNA export or by inhibition of splicing, or both, is still a matter of debate. We have addressed this issue in Xenopus laevis oocytes by microinjecting RNA molecules containing RRE along with purified recombinant Rev protein into the oocyte nuclei. Adenovirus pre-mRNA containing an RRE in the intron was spliced equally well in the absence and presence of Rev protein. Onty in the presence of Rev was non-spliced pre-mRNA exported from the nucleus; more surprisingly, the excised intron lariat (containing RRE) was also exported. Furthermore, an RRE-containing mRNA molecule that lacked intron sequences was also efficiently exported from the nucleus in a Rev-dependent manner. Therefore our results demonstrate that Rev can act directly at the level of nuclear export, independent of any inhibitory effect that it may exert on the splicing of pre-mRNA. Finally, our finding that the Rev mutant M10, shown previously to be inactive in human lymphoid cells, was also unable to export RRE-containing RNA molecules from oocyte nuclei suggests that one or more cellular factors, evolutionarily conserved between humans and Xenopus, interact with Rev in both cell systems to promote nuclear RNA export.

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Rev is necessary for translation but not cytoplasmic accumulation of HIV-1 vif, vpr, and env/vpu 2 RNAs.

Cited by 224 publications

References 37 publications

hRIP, a cellular cofactor for Rev function, promotes release of HIV RNAs from the perinuclear region

hRIP, a cellular cofactor for Rev function, promotes release of HIV RNAs from the perinuclear region

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

Evidence that HIV-1 Rev directly promotes the nuclear export of unspliced RNA.

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