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: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously showed that specific strains of human immunodeficiency virus (HIV)-1 infect the brain and contribute to Neuropathology, Cognitive Distress, and Neuropsychiatric Disease. To study further brain disease that results from HIV-1 infection, we commenced analysis of changes in gene expression in brain. We analyzed RNA purified from Frontal Cortex of 5 HIV-1 infected and 4 HIV-1 negative control subjects RNA was amplified and Affymetrix technology was used to analyze gene expression using the 12,585 gene Affymetrix Human Genome U95A chip. The expressed genes showed highly significant Pearsons correlations with each other within the two groups. Expression intensities were transferred to Microsoft Excel and Spotfire was used to analyze the results. Twenty-group K-means cluster analysis was done for HIV+ and HIV- subjects. Genes that were expressed in the same cluster numbers in the two groups were removed from further analysis. Analysis of Gene expression in the top 13 HIV+ clusters showed expression in the 40 gene categories designated in our prior studies. Genes from several categories occurred in more than one K-means cluster. Genes identified in these lists included several genes that have been previously studied: MBP, Myelin-PLP, NMDA receptor, MAG, astrocytic protein, Notch 3, APP, Senescence, proteasome, Ferritin, signaling, cell cycle, iNOS, Chemokine, splicing, synapse, protein tags, and ribosomal proteins. The first (primary significant) axis of both Principal Component Analyses ordered the genes in the same patient groups as the K-means cluster analysis for the respective patient groups. PCA was thus not more informative than K-Means cluster analysis. Ratios of HIV+ to HIV- intensities were calculated for all the averaged gene expression intensities. The ratio range was 0.14 to 9.26. The genes at the extremes (ad extrema) did not correspond to the gene order by K-means clustering (or PCA). The genes in the top 13 K-means clusters showed low-level changes by expression ratio. Genes ad extrema by ratio were in clusters with very large memberships. Mann-Whitney analysis confirmed expression ratio results. Several inferences result from our preliminary study. First, study design will be different in future studies involving additional replicates. Second, ratios inform us of the extent of changes in gene expression quantitatively. Third, Cluster methodology provides us with more subtle information, how bunches (clusters) of genes behave in terms of their centroids (attractors). Fourth, genes that change extensively by ratio tend to be in the larger k-Means clusters. We conclude that ranking gene expression with the use of expression ratio or by K-means clustering, yield different representations of the data.
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PMID:Analytic approaches to differential gene expression in AIDS versus control brains. 1535 27

While the Vif protein of human immunodeficiency virus type 1 (HIV-1) is essential for viral replication in non-permissive cells, it is rapidly degraded intracellularly. We have previously suggested that the rapid turn-over of Vif is biologically meaningful to prevent detrimental effects of this protein at high expression levels. We now studied the mechanism of Vif degradation by examining the blocking effect of protease inhibitors in pulse/chase experiments and by monitoring the extent of Vif ubiquitination. The rapid turn-over of Vif could be blocked by proteasome inhibitors, and Vif was highly ubiquitinated. Cytoskeletal Vif was found to be more stable than soluble cytosolic Vif. These degradation characteristics of Vif were cell type-independent and observed in both non-permissive and permissive cells. Characterization of a series of vif deletion mutants showed that amino acids predicted to be important for formation of beta-strand structures (amino acid nos. 63-70 and 86-89) were critical for maintaining a normal expression level of Vif and for viral infectivity. Finally, we performed comparative stability analysis of the four HIV-1 accessory proteins. Vif was unique in its short half-life and in the magnitude of the degradation. Taken together, we conclude that the proteasome degradation of HIV-1 Vif is a virologically important process and crucial for the function of Vif.
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PMID:Expression of HIV-1 accessory protein Vif is controlled uniquely to be low and optimal by proteasome degradation. 1537

The transcriptional coactivator lens epithelium-derived growth factor (LEDGF)/p75 acts as a chromatin tethering factor for human immunodeficiency virus type 1 (HIV-1) integrase protein, determining its nuclear localization and its tight association with nuclear DNA. Here we identify a second function for the LEDGF/p75-integrase interaction. We observed that stable introduction of HIV-1 integrase (IN) transcription units into cells made stringently LEDGF/p75-deficient by RNAi resulted in much lower steady state levels of IN protein than introduction into LEDGF/p75 wild type cells. The same LEDGF/p75-dependent disparity was observed for feline immunodeficiency virus IN. However, IN mRNA levels were equivalent in the presence and absence of LEDGF/p75. A post-translational mechanism was confirmed when the half-life of HIV-1 IN protein was found to be much shorter in LEDGF/p75-deficient cells. Proteasome inhibition fully countered this extreme instability, increasing IN protein levels to those seen in LEDGF/p75 wild type cells and implicating proteasomal destruction as the main cause of IN instability. Consistent with these data, increased ubiquitinated HIV-1 IN was found in the LEDGF/p75 knock-down cells. Moreover, restoration of LEDGF/p75 to knocked down clones rescued HIV-1 IN stability. Subcellular fractionation showed that HIV-1 IN is exclusively cytoplasmic in LEDGF/p75-deficient cells, but mainly nuclear in LEDGF/p75 wild type cells, and that cytoplasmic HIV-1 IN has a shorter half-life than nuclear HIV-1 IN. However, using LEDGF proteins defective for nuclear localization and IN interaction, we further determined that protection of HIV-1 IN from the proteasome requires neither chromatin tethering nor nuclear residence. Protection requires only interaction with LEDGF/p75, and it is independent of the subcellular localization of the IN-LEDGF complex.
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PMID:Lens epithelium-derived growth factor/p75 prevents proteasomal degradation of HIV-1 integrase. 1547 59

Enveloped virus budding has been linked to both the ubiquitin-proteasome pathway and the vacuolar protein-sorting pathway of cells. We show here for the paramyxovirus SV5 that proteasome inhibitors and expression of dominant-negative VPS4(E228Q) ATPase blocks budding. The SV5 matrix (M) protein lacks previously defined late domains (e.g., P[T/S]AP, PPxY, YPDL) that recruit cellular factors. We identified a new motif for budding (core sequence FPIV) that can compensate functionally for lack of a PTAP late domain in budding human immunodeficiency virus type 1 virus-like particles (VLPs). Mutagenesis experiments suggest the more general sequence O-P-x-V. The proline residue was found to be critically important for function of this sequence, as substitution of this proline in the SV5 M protein resulted in poor budding of SV5 VLPs and failure of recombinant SV5 virus to replicate normally. Adaptation of mutant virus occurred rapidly, resulting in new proline residues elsewhere in the M protein. We hypothesize that these proline residues act to partially restore virus budding by generation of new motifs that act as suboptimal late domains.
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PMID:Evidence for a new viral late-domain core sequence, FPIV, necessary for budding of a paramyxovirus. 1570 19

The lipid and metabolic disturbances associated with human immunodeficiency virus (HIV) protease inhibitor therapy in AIDS have stimulated interest in developing new agents that minimize these side effects in the clinic. The underlying explanation of mechanism remains enigmatic, but a recently described link between endoplasmic reticulum (ER) stress and dysregulation of lipid metabolism suggests a provocative integration of existing and emerging data. We provide new evidence from in vitro models indicating that proteasome inhibition and differential glucose transport blockade by protease inhibitors are proximal events eliciting an ER stress transcriptional response that can regulate lipogenic pathways in hepatocytes or adipocytes. Proteasome activity was inhibited in vitro by several protease inhibitors at clinically relevant (micromolar) levels. In the intact cells, protease inhibitors rapidly elicited a pattern of gene expression diagnostic of intracellular proteasome inhibition and activation of an ER stress response. This included induction of transcription factors GADD153, ATF4, and ATF3; amino acid metabolic enzymes; proteasome components; and certain ER chaperones. In hepatocyte lines, the ER stress response was closely linked to moderate increases in lipogenic and cholesterogenic gene expression. However, in adipocytes where GLUT4 was directly inhibited by some protease inhibitors, time-dependent suppression of lipogenic genes and triglyceride synthesis was observed in coordination with the ER stress response. These results further link ER stress to dyslipidemia and contribute to a unifying mechanism for the pathophysiology of protease inhibitor-associated lipodystrophy, helping explain differences in clinical metabolic profiles among protease inhibitors.
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PMID:Endoplasmic reticulum stress links dyslipidemia to inhibition of proteasome activity and glucose transport by HIV protease inhibitors. 1575 8

Prolonged treatments with inhibitors of human immunodeficiency(HIV)-encoded protease (ARPI) have been reported to induce early atherosclerotic events. Our in vitro study indicates that alpha-tocopherol may prevent drug-induced premature atherosclerosis since it interferes with CD36 scavenger receptor over-expression induced by ritonavir in monocytes. The mechanism of CD36 upregulation by ritonavir involves inhibition of the ubiquitin-proteasome system and alpha-tocopherol is able to normalize proteasome activity. These findings suggest that ARPI combined with early alpha-tocopherol supplementation may decrease the drug-induced atherosclerotic risk.
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PMID:HIV protease inhibitors-induced atherosclerosis: prevention by alpha-tocopherol. 1581 62

A recent study has provided important clues towards the identity of the host genes that conspire to promote post-integration latency of human immunodeficiency virus (HIV). Various genes controlling transcription, histone deacetylation and proteasome-mediated protein degradation have emerged as potential players. If the desired, but difficult, goal of complete virus eradication in HIV-infected patients is ever to be realized, the latent reservoir of HIV proviruses must be cleared. Understanding the molecular basis for viral latency is the key first step.
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PMID:Host factors regulating post-integration latency of HIV. 1581 80

The proteasomes of some protozoa are possible targets for chemotherapy. Leishmaniasis is a major health problem in human immunodeficiency virus (HIV) co-infected subjects. Two HIV protease inhibitors (PI), indinavir and saquinavir, have been shown to block proteasome functions; we therefore investigated their effects on the growth of two Leishmania spp. (Leishmania major and Leishmania infantum). After 24 h of treatment, both drugs exhibited a dose-dependent antileishmanial activity, with 50% lethal dose (LD50) values of, respectively, 8.3 microM and 7 microM on L. major; minor activity was observed on L. infantum. These results add new in vitro insights into the wide-spectrum efficacy of PI and suggest studying their action on amastigote forms of leishmania within macrophages in order to validate their potential contribution against opportunistic infections in treated seropositive patients.
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PMID:Antileishmanial activity of HIV protease inhibitors. 1595 71

Ubiquitin is highly conserved 76 amino acid protein found in all eukaryotic organisms and ubiquitin-proteasome pathway (UPP) plays a very important role in regulated non-lysosomal ATP dependent protein degradation. This pathway participates in or regulates numerous cellular processes, such as selective protein degradation, cell cycle progression, apoptosis, signal transduction, transcriptional regulation, receptor control by endocytosis, immune response and the processing of antigens. Nevertheless, roles of UPP in virus infection are only beginning to be clarified. Ubiquitin homology has also been found in insect viruses. All viral ubiquitin genes encode an N-terminal ubiquitin sequence and 3-256 amino acids C-terminal peptides. Most of the residues known to be essential for ubiquitin function have been conserved in the viral variant. In Autographa californica nucleopolyhedrovirus (AcMNPV), viral ubiquitin is attached to the inner surface of budded viron membrane by a covalently linked phospholipid and is not essential for viral replication. Currently, insect viruses are the only viruses known to encode ubiquitin. However, ubiquitin also plays a role in the life cycle of other viruses. Host ubiquitin molecules have been found in some plant viruses and other animal viruses. Additionally, Africa swine fever virus (ASFV) encodes a ubiquitin-conjugating enzyme (E2) and a putative causal link between human immunodeficiency virus type 1 (HIV-1) and ubiquitin was established by showing that depletion of the intracellular pool of free ubiquitin inhibits the virus budding. Further analyses indicated that many retroviruses proteins which are required for efficient pinching off the virus bud contain a late domain. The core element of the late domain is a proline-rich motif (PPXY) which mediates the late domain to be ubiquitinated by cellular proteins. Recently, it has been shown that many retroviruses have developed mechanisms to escape the cellular immune response, to facilitate virus replication and to promote virus assembly and budding via host UPP.
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PMID:[Ubiquitin-proteasome pathway and virus infection]. 1596

Retroviral late (L) domains present within Gag act in conjunction with cellular proteins to efficiently release virions from the surface of the cell. Three different critical core sequences have been identified as required elements for L-domain function: PPPY, PTAP (also PSAP), and YPDL, with different retroviruses utilizing one or two of these core sequences. The human immunodeficiency virus type 1 (HIV-1) L domain is centered around a PTAP sequence in the p6 region of Gag. To assess the ability of heterologous L-domain sequences to be functionally interchanged for those in full-length HIV-1, we produced a series of constructs that replaced PTAP-containing p6(Gag) sequences with those of PPPY- or YPDL-based L domains. While previous studies had found that L domains are interchangeable in other retroviruses, most of the sequences introduced into p6(Gag) failed to substitute for PTAP-mediated L-domain function. One exception was the 11-amino-acid p2b sequence of Rous sarcoma virus (RSV) Gag, which could fully restore HIV-1 budding, while a PPPPY sequence exchange alone did not. This suggests that the RSV L domain consists of more than simply its core L-domain sequence. The HIV-p2b chimera was as infectious as the wild type, produced normal virions, and was sensitive to proteasome inhibitors. These results show that L-domain sequences are not necessarily interchangeable. Thus, HIV-1 Gag might have a more stringent requirement for L-domain function than the other retroviruses previously studied.
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PMID:Heterologous late-domain sequences have various abilities to promote budding of human immunodeficiency virus type 1. 1599 97


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