Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The herpes simplex virus type 1 tegument protein known as VP13/14, or hUL47, localizes to the nucleus and binds RNA. Using fluorescence loss in photobleaching analysis, we show that hUL47 undergoes nucleocytoplasmic shuttling during infection. We identify the hUL47 nuclear export signal (NES) as a C-terminal 10-residue hydrophobic peptide and measure its efficiency relative to that of the classical human immunodeficiency virus type 1 Rev NES. Finally, we show that the hUL47 NES is sensitive to the inhibitor of CRM1-mediated nuclear export leptomycin B. Hence, hUL47 joins a growing list of virus-encoded RNA-binding proteins that use CRM1 to exit the nucleus.
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PMID:Characterization of a CRM1-dependent nuclear export signal in the C terminus of herpes simplex virus type 1 tegument protein UL47. 1871 12

CRM1-mediated nucleocytoplasmic transport plays an important role in many cellular processes and diseases. To investigate the structural basis required for the inhibition of the CRM1-mediated nuclear export we have synthesized analogs of a previously identified small molecule lead compound and monitored their activity against the Rev function of the human immunodeficiency virus. Microscopy studies show that the active congeners of this series inhibit the nucleocytoplasmic transport of Rev and the co-localization between Rev and CRM1 in living cells. Mechanism of action studies show their interaction with the Cys528 residue of CRM1 involving a Michael-addition type of reaction. However, structure-activity relationship demonstrates strict constraints to the structure of the inhibitors, and shows that activity is not solely correlated to Michael-addition suggesting a more complex mechanism of action. Our results are suggestive for the existence of a well-defined interaction at the CRM1-NES binding site. In addition, the most selective congener inhibited the HIV-1 production in latently infected cells. These specific CRM1 inhibitors are of interest as tool for analyzing the mechanisms of post-transcriptional control of gene expression and provide insight in the design of new agents.
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PMID:Inhibition of the CRM1-mediated nucleocytoplasmic transport by N-azolylacrylates: structure-activity relationship and mechanism of action. 1883 18

Nup358 (also known as RanBP2), a component of the cytoplasmic filaments of the nuclear pore complex, has been implicated in various nucleocytoplasmic transport pathways. Here, we identify Nup358 as an important factor for transportin-mediated nuclear import. Depletion of Nup358 resulted in a strong inhibition of nuclear import of the human immunodeficiency virus type 1 (HIV-1) Rev protein. HIV-1 Rev is an RNA-binding protein that is required for CRM1 (also known as exportin 1)-dependent nuclear export of unspliced or partially spliced viral RNA. We show that transportin is the major nuclear import receptor for HIV-1 Rev in HeLa cells. Overexpression of transportin strongly promoted nuclear import of HIV-1 Rev in Nup358-depleted cells, indicating that the import receptor becomes rate-limiting under these conditions. Importantly, the import rate of other transportin-dependent proteins was also significantly reduced in Nup358-depleted cells. Our data therefore suggest a general role for Nup358 in transportin-mediated nuclear import.
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PMID:The nuclear pore component Nup358 promotes transportin-dependent nuclear import. 1929 63

Jaagsiekte sheep retrovirus (JSRV) is a simple betaretrovirus causing a contagious lung cancer of sheep. JSRV encodes unspliced and spliced viral RNAs, among which unspliced RNA encodes Gag and Pol proteins and a singly spliced mRNA encodes Env protein. In another study we found that JSRV encodes a regulatory protein, Rej, that is responsible for synthesis of Gag polyprotein from unspliced viral RNA. Rej is encoded in the 5' end of env, and it enhances nuclear export or accumulation of cytoplasmic unspliced viral RNA in 293T cells but not in most other cell lines (A. Hofacre, T. Nitta, and H. Fan, J. Virol. 83:12483-12498, 2009). In this study, we found that mutations in the 3' end of env in the context of a cytomegalovirus-driven full-length JSRV expression construct abolished Gag protein synthesis and released viruses in 293T cells. These mutants also showed deficits in accumulation of unspliced viral RNA in the cytoplasm. These mutants defined a Rej-responsive element (RejRE). Inhibition of CRM1 but not Tap function prevented nuclear export/accumulation of cytoplasmic unspliced RNA in 293T cells, similarly to other complex retroviruses that express analogous regulator proteins (e.g., human immunodeficiency virus Rev). Structural modeling of the RejRE with Zuker M-fold indicated a region with a predicted stable secondary structure. Mutational analysis in this region indicated the importance of both secondary structures and primary nucleotide sequences in a central stem-bulge-stem structure. In contrast to 293T cells, mutations in the RejRE did not affect the levels of cytoplasmic unspliced RNA in 293 cells, although the unspliced RNA showed partial degradation, perhaps due to lack of translation. RejRE-containing RNA relocalized Rej protein from the nucleus to the cytoplasm in 293 and rat 208F cells, suggesting binding of Rej to the RejRE.
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PMID:Identification and mutational analysis of a Rej response element in Jaagsiekte sheep retrovirus RNA. 1977 34

Expression of the human immunodeficiency virus type 1 (HIV-1) Rev protein is essential for completion of the viral life cycle. Rev mediates nuclear export of partially spliced and unspliced viral transcripts and therefore bears a nuclear localization signal (NLS) as well as a nuclear export signal (NES), which allow its nucleocytoplasmic shuttling. Attempts to express the wild-type Rev protein in eukaryotic human cultured cells have encountered difficulties and so far have failed. Here we show that accumulation of Rev, which occurs in nondividing Rev-expressing cells or when such cells reach confluency, results in death of these cells. Cell death was also promoted by addition of a cell permeable peptide bearing the Rev-NES sequence, but not by the Rev-NLS peptide. Our results probably indicate that binding of excess amounts of the Rev protein or the NES peptide to the exportin receptor CRM1 results in cells' death.
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PMID:Over-expression of the HIV-1 Rev promotes death of nondividing eukaryotic cells. 2015 Nov 87

The human immunodeficiency virus, type 1 (HIV-1)-encoded Rev protein is essential for the expression of late viral mRNAs. Rev forms a large organized multimeric protein-protein complex on the Rev response element of these viral mRNA species and transports them from the nucleus to the cytoplasm, exploiting the CRM1-mediated cellular machinery. Here we report the selection of a nanobody, derived from a llama heavy-chain only antibody, that efficiently blocks the assembly of Rev multimers. The nanobody inhibits HIV-1 replication in cells and specifically suppresses the Rev-dependent expression of partially spliced and unspliced HIV-1 RNA. In HIV-susceptible cells, this nanobody thus has potential as an effective anti-HIV agent using genetic immunization strategies. Its binding site was mapped to Rev residues Lys-20 and Tyr-23 located in the N-terminal alpha-helical multimerization domain. In the presence of this nanobody, we observed an accumulation of dimeric Rev species, supporting a head-to-head/tail-to-tail molecular model for Rev assembly. The results indicate that the oligomeric assembly of Rev follows an ordered stepwise process and identify a new epitope within Rev that could guide strategies for the development of novel HIV inhibitors.
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PMID:An intrabody based on a llama single-domain antibody targeting the N-terminal alpha-helical multimerization domain of HIV-1 rev prevents viral production. 2040 3

The human immunodeficiency virus type 1 (HIV-1) regulatory protein, Rev, mediates the nuclear export of unspliced gag and singly spliced env mRNAs by bridging viral RNA and the export receptor, CRM1. Recently, rat CRM1 was found to be less efficient than human CRM1 in supporting Rev function in rats. In this study, to understand the role of CRM1 in HIV propagation, the mechanism underlying the function of human and rat CRM1 in HIV-1 replication was investigated in rat cells. The production of viral particles, represented by the p24 Gag protein, was greatly enhanced by hCRM1 expression in rat cells; however, this effect was not simply because of the enhanced export of gag mRNA. The translation initiation rate of gag mRNA was not increased, nor was the Gag protein stabilized in the presence of hCRM1. However, the processing of the p55 Gag precursor and the release of viral particles were facilitated. These results indicated that hCRM1 exports gag mRNA to the cytoplasm, not only more efficiently than rCRM1 but also correctly, leading to efficient processing of Gag proteins and particle formation.
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PMID:Nuclear and cytoplasmic effects of human CRM1 on HIV-1 production in rat cells. 2125 Nov 65

Human immunodeficiency virus (HIV)-1 encoded Rev is essential for export from the nucleus to the cytoplasm, of unspliced and singly spliced transcripts coding for structural and nonstructural viral proteins. This process is spatially and temporally coordinated resulting from the interactions between cellular and viral proteins. Here we examined the effects of the sub-cellular localization and dynamics of Rev on the efficiency of nucleocytoplasmic transport of HIV-1 Gag transcripts and virus particle production. Using confocal microscopy and fluorescence recovery after bleaching (FRAP), we report that NF90ctv, a cellular protein involved in Rev function, alters both the sub-cellular localization and dynamics of Rev in vivo, which drastically affects the accumulation of the viral protein p24. The CRM1-dependent nuclear export of Gag mRNA linked to the Rev Response Element (RRE) is dependent on specific domains of the NF90ctv protein. Taken together, our results demonstrate that the appropriate intracellular localization and dynamics of Rev could regulate Gag assembly and HIV-1 replication.
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PMID:Production of HIV particles is regulated by altering sub-cellular localization and dynamics of Rev induced by double-strand RNA binding protein. 2136 84

Retroviruses assemble new virus particles that are released by budding from the plasma membranes of infected cells. Gag proteins, encoded by retroviruses, orchestrate the assembly of virus particles in close collaboration with host cell machinery. The earliest steps in retrovirus assembly-those immediately following synthesis of Gag on cytosolic ribosomes-are poorly understood. Rous sarcoma virus (RSV) offers a unique model system for dissecting these early steps because the RSV Gag protein undergoes transient nuclear trafficking prior to plasma membrane transport. Other Gag proteins, including those of human immunodeficiency virus (HIV), murine leukemia virus (MLV), foamy virus and retrotransposons in Schizosaccharomyces pombe and Drosophila, have also been detected in the nucleus, suggesting that nuclear trafficking of Gag proteins is a common property of retroviruses and retrotransposons. In addition to retroviruses, many structural proteins of unrelated viruses, including influenza M1, NEP and NP proteins,38 Borna disease virus N and P proteins28,56 and coronavirus N protein,23,57 undergo nuclear localization and bind viral RNAs to form viral ribonuclear protein (RNP) complexes that are exported from the nucleus for packaging into virus particles. Similarly, nuclear trafficking of the RSV Gag protein is required for efficient encapsidation of the viral genomic RNA (gRNA) into assembling virus particles.19 Recently, we reported that the viral RNA itself appears to be a key factor in controlling the nucleus/cytosol distribution of RSV Gag.22 Our data demonstrate that binding of RSV RNA to the Gag protein promotes Gag-CRM1-RanGTP binding, resulting in export of the retroviral RNP from the nucleus. We propose that association of the viral RNA induces a conformational change in Gag that reveals its nuclear export signal (NES) and prepares that complex for its journey to the plasma membrane for budding. This work challenges existing dogmas regarding the molecular basis of Gag-mediated selection of gRNA for packaging and may lead to novel paradigms for the mechanism of retroviral genome encapsidation.
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PMID:New insights into the nuclear localization of retroviral Gag proteins. 2173 31

Influenza A virus uses cellular protein transport systems (e.g., CRM1-mediated nuclear export and Rab11-dependent recycling endosomes) for genome trafficking from the nucleus to the plasma membrane, where new virions are assembled. However, the detailed mechanisms of these events have not been completely resolved, and additional cellular factors are probably required. Here, we investigated the role of the cellular human immunodeficiency virus (HIV) Rev-binding protein (HRB), which interacts with influenza virus nuclear export protein (NEP), during the influenza virus life cycle. By using small interfering RNAs (siRNAs) and overexpression of a dominant negative HRB protein fragment, we show that cells lacking functional HRB have significantly reduced production of influenza virus progeny and that this defect results from impaired viral ribonucleoprotein (vRNP) delivery to the plasma membrane in late-stage infection. Since HRB colocalizes with influenza vRNPs early after their delivery to the cytoplasm, it may mediate a connection between the nucleocytoplasmic transport machinery and the endosomal system, thus facilitating the transfer of vRNPs from nuclear export to cytoplasmic trafficking complexes. We also found an association between NEP and HRB in the perinuclear region, suggesting that NEP may contribute to this process. Our results identify HRB as a second endosomal factor with a crucial role in influenza virus genome trafficking, suggest cooperation between unique endosomal compartments in the late steps of the influenza virus life cycle, and provide a common link between the cytoplasmic trafficking mechanisms of influenza virus and HIV.
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PMID:Human immunodeficiency virus rev-binding protein is essential for influenza a virus replication and promotes genome trafficking in late-stage infection. 2175 12


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