Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rous sarcoma virus (RSV), a simple retrovirus, needs to export unspliced viral RNA from the nucleus to the cytoplasm, circumventing the host cell restriction on cytoplasmic expression of intron-containing RNA. The cytoplasmic accumulation of full-length viral RNA is promoted by two cis-acting direct repeat (DR) elements that flank the src gene; at least one copy of the DR sequence is necessary for viral replication. We show here that the DR mediates export of a reporter construct from the nucleus, suggesting it is a constitutive transport element (CTE). In contrast, human immunodeficiency virus type 1 (HIV-1) and other complex retroviruses encode accessory proteins, Rev or Rex, which promote export of incompletely spliced viral transcripts. This RNA export pathway is CRM1 dependent and can be blocked by the cytotoxic agent leptomycin B. We show here that DR-mediated export is CRM1 independent, suggesting that RSV uses a different export pathway from that of HIV-1 and other complex retroviruses. The simian retroviruses have a CTE which interacts with the cellular Tap export protein. However, we were unable to detect binding of the RSV DR RNA to Tap, suggesting it may use a different export pathway from that of the simian retroviruses. These data suggest that the RSV DR element uses a novel nucleocytoplasmic export pathway.
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PMID:Rous sarcoma virus DR posttranscriptional elements use a novel RNA export pathway. 1100 Feb 20

It was recently reported that the human endogenous retrovirus HTDV/HERV-K encodes the regulatory protein Rec (formerly designated Corf), which is functionally equivalent to the nuclear export adapter proteins Rev of human immunodeficiency virus and Rex of human T-cell leukemia virus. We have demonstrated that the Rec protein interacts with a characteristic 429-nucleotide RNA element, the Rec-responsive element (RcRE), present in the 3' long terminal repeat of HTDV/HERV-K transcripts. In analogy to the Rev and Rex proteins, which have distinct RNA binding sites in their responsive elements, we have proposed that Rec may also have a defined binding site in the RcRE. In this report, we demonstrate that not every HTDV/HERV-K copy present in the human genome contains an active RcRE, and we characterize mutations that abrogate Rec function. In addition, we demonstrate that Rec function requires binding to a complex, folded RNA structure rather than binding to a discrete specific binding site, in contrast to Rev and Rex and their homologous responsive elements. We define four stem-loop structures in the RcRE that are essential for Rec function. Finally, we demonstrate that both Rev and Rex can mediate nuclear export through the RcRE but that their binding sites are different from each other and from that of Rec.
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PMID:Rec (formerly Corf) function requires interaction with a complex, folded RNA structure within its responsive element rather than binding to a discrete specific binding site. 1158 4

The human T cell leukemia virus, type 1 (HTLV-1), Rex protein mediates the nuclear export of unspliced and incompletely spliced viral mRNAs. This post-transcriptional activity is dependent in part on the binding of this protein to cis-regulatory sequences termed the Rex-response element (XRE). We have proposed previously that the decreased functionality exhibited by Rex in human lymphoblastoid Jurkat T cells may be linked to alterations in the Rex/XRE interactions. The analysis of the ribonucleoprotein complexes formed between Jurkat nuclear proteins and XRE-RNA led to the identification of a 36-kDa protein as heterogeneous nuclear ribonucleoprotein (hnRNP) A1. In vitro binding assays revealed that hnRNP A1 proteins were found to interfere with the binding of Rex to XRE, whereas nuclear extracts depleted of these proteins were unable to disrupt Rex-XRE complexes. Furthermore, A1 proteins from Jurkat cells were acting in a concentration-dependent manner, suggesting that the amount of these RNA-binding proteins is a critical parameter in controlling Rex activity. We indeed observed a lower level of hnRNP A1 in in vitro HTLV-1-transformed virus-producing T cells than that detected in Jurkat cells. Likewise, overexpression of hnRNP A1 proteins in 293T cells and in Jurkat cells led to a decrease in the expression of a reporter gene dependent on Rex/XRE interactions. Such a decrease was not observed when the expression of the same reporter gene by cells overexpressing hnRNP A1 was dependent on the interactions of human immunodeficiency virus Rev protein with the Rev-response element. These findings indicate that hnRNP A1 by competing with Rex for the formation of REX-XRE complexes is specifically involved in the modulation of the post-transcriptional activity of Rex.
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PMID:Heterogeneous nuclear ribonucleoprotein A1 interferes with the binding of the human T cell leukemia virus type 1 rex regulatory protein to its response element. 1189 30

The human immunodeficiency virus type 1 (HIV-1) Rev and human T-cell leukemia virus type 1 (HTLV-1) Rex proteins are essential for the expression of viral structural proteins and productive infection. Both contain a nuclear export signal (NES) in their C-terminal domain and a nuclear localization signal (NLS) in their N-terminal domain. The NES and NLS are necessary for shuttling between nucleus and cytoplasm and are therefore indispensable for the transport of unspliced and singly spliced viral transcripts. HIV-1 Rev function is restricted in A9 cells, a murine fibroblast cell line, whereas HTLV-1 Rex is functional in these cells. Immunofluorescence studies with RevGFP fusion protein demonstrate normal import and export of Rev in A9 cells. To ascertain which domains of Rev are necessary for the restriction of Rev function in A9 cells, we studied a chimeric construct in which the NES domain of Rev was exchanged with Rex C-terminal amino acids 79 to 95, the Rev1-79/Rex79-95 chimera, which restored Rev function in A9 cells. In addition, overexpression of a truncated Rev containing the Rev C-terminal domain in the presence of wild-type Rev, led to restoration of Rev function in A9 cells. These results suggest that the C-terminal domain of HIV-1 Rev plays an important role in restricting Rev function in murine cells.
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PMID:Restriction of human immunodeficiency virus type 1 Rev function in murine A9 cells involves the Rev C-terminal domain. 1258 34

The Rev protein of human immunodeficiency virus type 1 (HIV-1) is essential for the nucleocytoplasmic transport of unspliced and partially spliced HIV mRNAs containing the Rev response element (RRE). In a yeast two-hybrid screen of a HeLa cell-derived cDNA expression library for human factors interacting with the Rev leucine-rich nuclear export sequence (NES), we identified a kinesin-like protein, REBP (Rev/Rex effector binding protein), highly homologous to Kid, the carboxy-terminal 75-residue region of which interacts specifically with the NESs of HIV-1 Rev, human T-cell leukemia virus type 1 Rex, and equine infectious anemia virus Rev but not with functionally inactive mutants thereof. REBP is a nuclear protein that colocalizes with Rev in the nucleoplasm and nuclear periphery of transfected cells. Specific, albeit weak, interaction between REBP and Rev could be demonstrated in coimmunoprecipitation assays in BSC-40 cells. REBP can modestly enhance Rev-dependent RRE-linked reporter gene expression both independently and in cooperation with the nucleoporin cofactor Rab/hRIP. Thus, REBP displays the characteristics expected of an authentic mediator of Rev NES function and may play a role in RRE RNA transport during HIV infection.
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PMID:A nuclear kinesin-like protein interacts with and stimulates the activity of the leucine-rich nuclear export signal of the human immunodeficiency virus type 1 rev protein. 1280 22

The ataxia-telangiectasia-mutated (ATM) kinase plays a central role in responses to various forms of DNA damage and has been suggested to facilitate human immunodeficiency virus type 1 (HIV-1) integration. Here, we describe a series of experiences that indicate that ATM can enhance HIV-1 replication by stimulating the action of the Rev viral posttranscriptional regulator. The Rev-dependent stimulation of viral late gene expression was observed with ATM-overexpressing cells, a result confirmed with a Rev-dependent reporter construct. Both parameters were also enhanced upon treatment of HeLa cells with caffeine, a xanthine that, in this cellular context, stimulates ATM activity. As well, decreased levels of virions with reduced infectivity were released by ATM knockdown cells. Notably, ATM overexpression did not stimulate the HIV-1 late gene expression within the context of Rev-independent constructs or the Rex-dependent production of capsid from human T-cell leukemia virus type 1 proviral constructs. Altogether, these results indicate that ATM can positively influence HIV-1 Rev function.
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PMID:Ataxia-telangiectasia-mutated (ATM) protein can enhance human immunodeficiency virus type 1 replication by stimulating Rev function. 1647 51

Human immunodeficiency virus Rev-binding protein (HRB), also called human Rev-interacting protein (hRIP) or Rev/Rex activation domain binding (RAB) is a partner of the tyrosine kinase substrate EPS15, and it has been recovered in the AP-2 interactome. EPS15 and AP-2 are involved in endocytosis, but the function of HRB in this process is still unknown. Here we identified HRB as a partner of the vesicular SNARE tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP, also called VAMP7) in yeast two-hybrid screens and using biochemical assays. In HeLa cells, HRB localized both in the nucleus and in the cytoplasm. In the cytoplasm, HRB colocalized with clathrin-, AP-2-, EPS15-, and transferrin receptor-containing vesicles. We did not see significant colocalization between HRB and TI-VAMP in HeLa cells, and we saw partial colocalization with green fluorescent protein-TI-VAMP in stably expressing Madin-Darby canine kidney cells. Nevertheless using a pHLuorin-tagged TI-VAMP construct, we found that HRB and TI-VAMP colocalize close to the plasma membrane after 5 min of anti-green fluorescent protein antibody uptake. These results suggest that TI-VAMP and HRB may interact only during the early stages of endocytosis. Furthermore uptake experiments followed by fluorescence-activated cell sorting showed that the endocytosis of fluorescent transferrin and pHLuorin-TI-VAMP is strongly reduced in HRB knockdown cells. Altogether these results suggest that HRB is involved in clathrin-dependent endocytosis and recruits TI-VAMP in this process.
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PMID:Role of HRB in clathrin-dependent endocytosis. 1881 12

Retroviruses have evolved mechanisms for transporting their intron-containing RNAs (including genomic and messenger RNAs, which encode virion components) from the nucleus to the cytoplasm of the infected cell. Human retroviruses, such as human immunodeficiency virus (HIV) and human T cell leukemia virus type 1 (HTLV-1), encode the regulatory proteins Rev and Rex, which form a bridge between the viral RNA and the export receptor CRM1. Recent studies show that these transport systems are not only involved in RNA export, but also in the encapsidation of genomic RNA; furthermore, they influence subsequent events in the cytoplasm, including the translation of the cognate mRNA, transport of Gag proteins to the plasma membrane, and the formation of virus particles. Moreover, the mode of interaction between the viral and cellular RNA transport machinery underlies the species-specific propagation of HIV-1 and HTLV-1, forming the basis for constructing animal models of infection. This review article discusses recent progress regarding these issues.
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PMID:Role of Nucleocytoplasmic RNA Transport during the Life Cycle of Retroviruses. 2278 32


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