Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis B surface antigen (HBsAg) is the major component of the envelope of hepatitis B virus (HBV). As a resident membrane protein in the endoplasmic reticulum, it plays a key role in the viral morphogenesis. Little is known about cellular proteins that interact with HBsAg and thereby contributing to HBV morphogenesis. Using the yeast split-ubiquitin system, a number of cellular membrane proteins have been isolated in this study. These include a resident protein of endoplasmic reticulum (thioredoxin-related transmembrane protein 2), an adaptor protein involved in clathrin-mediated endocytosis and HIV-mediated downregulation of CD4, and a co-receptor of coxsakie B virus. The significance of our findings is suggested by the identification of cellular membrane proteins interacting with other virus proteins. Further functional analysis of these HBsAg- interacting cellular membrane proteins should shed new insights on their role in HBV morphogenesis.
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PMID:Identification of cellular membrane proteins interacting with hepatitis B surface antigen using yeast split-ubiquitin system. 1600 63

The human immunodeficiency virus type 1, HIV-1, has long been known to possess the viral infectivity factor, Vif, which supports productive viral replication in non-permissive cells, such as peripheral blood lymphocytes (PBL). In the last few years, Vif function has been elucidated by the finding that it inactivates a cellular anti-viral factor named APOBEC3G. Tremendous progress has been made since the initial observation, reflected in a large number of publications. APOBEC3G represents a novel innate defense mechanism against retroviral infection. It is expressed in non-permissive cells and possesses cytidine deaminase activity. APOBEC3G is encapsidated into viral particles and is transported into the infected cell, where it facilitates the deamination of the cytosine residues in the first strand cDNA intermediate during early steps of HIV infection. Vif counteracts APOBEC3G by direct binding, which mediates its degradation by the ubiquitin-dependent proteasomal pathway. In this review, we will summarize the current knowledge about the structure and function of both proteins, their interaction with each other and the mechanism of Vif-mediated APOBEC3G inactivation. In addition, we will discuss possible interference strategies as potential new drugs against HIV infection.
Curr HIV Res 2005 Oct
PMID:HIV-1 Vif: HIV's weapon against the cellular defense factor APOBEC3G. 1625 Aug 85

APOBEC3 proteins are antiviral host factors for a wide variety of retroviruses. HIV-1 Vif overcomes the antiviral activity of APOBEC3G by ubiquitinating the protein. In this study, we examined the ability of Vif to antagonize other family members of APOBEC3 proteins, together with its mechanism. Using HIV infectivity, virion incorporation, immunoprecipitation, and in vitro ubiquitin conjugation assays, we show that the ability of Vif to inhibit antiviral activity of APOBEC3 proteins positively correlates with its ability to bind and ubiquitinate these proteins by a Vif-Cullin5-ElonginB-ElonginC (Vif-BC-Cul5) complex. These results suggest that Vif exhibits its anti-APOBEC3 activity by the ubiquitin ligase activity of the Vif-BC-Cul5 complex.
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PMID:Ubiquitination of APOBEC3 proteins by the Vif-Cullin5-ElonginB-ElonginC complex. 1630 61

The UEV domain of the TSG101 protein functions in the vacuolar protein-sorting pathway and in the budding process of HIV-1 and other retroviruses by recognizing ubiquitin in proteins tagged for degradation and short sequences in viral proteins containing an essential and well conserved PTAP motif, respectively. A deep understanding of these interactions is key to the rational design of much-needed novel antivirals. Here, the crystal structure of the TSG101 UEV domain (TSG101-UEV) is presented. TSG101-UEV was crystallized in the presence of PEG 4000 and ammonium sulfate. Under these conditions, crystals were obtained in space group R3, with unit-cell parameters a = b = 97.9, c = 110.6 A, alpha = beta = 90, gamma = 120 degrees . Phases were solved by molecular replacement and the crystal structure of TSG101-UEV was refined to an R factor of 18.8% at 2.2 A resolution. A comparison between the crystal structure and previously reported NMR structures has revealed significant differences in the conformation of one of the loops implicated in ubiquitin recognition. Also, the resulting structure has provided information about the presence of water molecules at the binding interface that could be of relevance for peptide recognition.
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PMID:Structure of human TSG101 UEV domain. 1655 48

APOBEC3G is a potent antiretroviral factor, which belongs to the APOBEC superfamily of cytidine deaminases. It deaminates cytidine to uridine in nascent minus-strand viral DNA, inducing G-to-A hypermutation in the plus-strand viral DNA. HIV-1 Vif protein overcomes the antiviral activity of APOBEC3G by targeting it for ubiquitin-dependent degradation. Recent accumulating evidences that other members of APOBEC proteins also show antiviral activity on a wide variety of viruses suggest that APOBEC family proteins play a crucial role in an antiviral defense as an innate immunity. Here, we review recent progress in research on APOBEC3 proteins.
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PMID:[Antiviral defense by APOBEC3 family proteins]. 1655 12

The "class E" vacuolar protein sorting (VPS) pathway mediates sorting of ubiquitinated cargo into the forming vesicles of the multivesicular bodies (MVB), and it is essential for down-regulation of signaling by growth factors and budding of enveloped viruses such as Ebola and HIV-1. Work in yeast has identified DOA4 as a gene that is recruited by the class E machinery to remove ubiquitin from the endosomal cargo before it is incorporated into MVB vesicles, but the identity of the mammalian counterpart is unclear. Here we report the interaction of AMSH (associated molecule with the SH3 domain of STAM), an endosomal deubiquitinating enzyme, with the endodomal sorting complex required for transport (ESCRT-III) subunits CHMP1A, CHMP1B, CHMP2A, and CHMP3. We also show that a catalytically inactive AMSH inhibits retroviral budding in a dominant-negative manner and induces the accumulation of ubiquitinated forms of an endosomal cargo, namely murine leukemia virus Gag. Finally, VPS4 and AMSH compete for binding to the C-terminal regions of CHMP1A and CHMP1B, revealing a coordinated interaction with ESCRT-III. Taken together, these results are consistent with a role of AMSH in the deubiquitination of the endosomal cargo preceding lysosomal degradation.
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PMID:Interaction of AMSH with ESCRT-III and deubiquitination of endosomal cargo. 1676 Apr 79

The p6 domain of human immunodeficiency virus type 1 (HIV-1) Gag has long been known to be monoubiquitinated. We have previously shown that the MA, CA, and NC domains are also monoubiquitinated at low levels (E. Gottwein and H. G. Krausslich, J. Virol. 79:9134-9144, 2005). While several lines of evidence support a role for ubiquitin in virus release, the relevance of Gag ubiquitination is unclear. To directly address the function of Gag ubiquitination, we constructed Gag variants in which lysine residues in the NC, SP2, and p6 domains were mutated to arginine either in individual domains or in combination. Using these mutants, we showed that in addition to MA, CA, NC, and p6, SP2 is also mono- or di-ubiquitinated at levels comparable to those of the other domains. Replacement of all lysine residues in only one of the domains had minor effects on virus release, while cumulative mutations in NC and SP2 or in NC and p6 resulted in an accumulation of late budding structures, as observed by electron microscopy analysis. Strikingly, replacement of all lysine residues downstream of CA led to a significant reduction in virus release kinetics and a fivefold accumulation of late viral budding structures compared to wild-type levels. These results indicate that ubiquitination of lysine residues in Gag in the vicinity of the viral late domain is important for HIV-1 budding, while no specific lysine residue may be needed and individual domains can functionally substitute. This is consistent with Gag ubiquitination being functionally involved in a transient protein interaction network at the virus budding site.
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PMID:Cumulative mutations of ubiquitin acceptor sites in human immunodeficiency virus type 1 gag cause a late budding defect. 1677 14

APOBEC3G (A3G) is an antiretroviral host factor that functions by deaminating dC to dU in retroviral cDNA. HIV-1 Vif protein counteracts A3G via a ubiquitin-proteasome pathway. In the case of a simple retrovirus such as the murine leukemia virus (MLV), it remains unclear why it can replicate in cells expressing APOBEC3 (A3) even though it doesn't possess any accessory proteins such as Vif. In this study, we demonstrate that MLV escapes from murine A3 (mA3) via two distinct novel mechanisms. First, viral RNA (vRNA) blocks the binding of mA3 to Gag, resulting in the exclusion of mA3 from MLV virions. Second, viral protease (vPR) cleaves mA3 after maturation of virions. Here, we suggest that each virus has its own strategy to escape from A3 proteins and that these mechanisms might be used by other viruses that do not possess Vif-like protein. On the other hand, mice possess another form of mA3, delta exon5, that escapes from the cleavage by vPR to show more antiviral activity than the wild type mA3. This also suggests that battles between host intrinsic immunity and viruses have led to the evolution of proteins on both sides.
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PMID:Murine retrovirus escapes from murine APOBEC3 via two distinct novel mechanisms. 1689 May 33

The neuronal ubiquitin/proteasomal pathway has been implicated in the pathogenesis of Alzheimer's disease (AD). We now show that a component of the pathway, ubiquitin C-terminal hydrolase L1 (Uch-L1), is required for normal synaptic and cognitive function. Transduction of Uch-L1 protein fused to the transduction domain of HIV-transactivator protein (TAT) restores normal enzymatic activity and synaptic function both in hippocampal slices treated with oligomeric Abeta and in the APP/PS1 mouse model of AD. Moreover, intraperitoneal injections with the fusion protein improve the retention of contextual learning in APP/PS1 mice over time. The beneficial effect of the Uch-L1 fusion protein is associated with restoration of normal levels of the PKA-regulatory subunit IIalpha, PKA activity, and CREB phosphorylation.
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PMID:Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory. 1692 86

Human immunodeficiency virus type 1 (HIV-1) infects CD4(+) T lymphocytes and monocytes/macrophages, incorporating host proteins in the process of assembly and budding. Analysis of the host cell proteins incorporated into virions can provide insights into viral biology. We characterized proteins in highly purified HIV-1 virions produced from human monocyte-derived macrophages (MDM), within which virus buds predominantly into intracytoplasmic vesicles, in contrast to the plasmalemmal budding of HIV-1 typically seen with infected T cells. Liquid chromatography-linked tandem mass spectrometry of highly purified virions identified many cellular proteins, including 33 previously described proteins in HIV-1 preparations from other cell types. Proteins involved in many different cellular structures and functions were present, including those from the cytoskeleton, adhesion, signaling, intracellular trafficking, chaperone, metabolic, ubiquitin/proteasomal, and immune response systems. We also identified annexins, annexin-binding proteins, Rab proteins, and other proteins involved in membrane organization, vesicular trafficking, and late endosomal function, as well as apolipoprotein E, which participates in cholesterol transport, immunoregulation, and modulation of cell growth and differentiation. Several tetraspanins, markers of the late endosomal compartment, were also identified. MDM-derived HIV contained 26 of 37 proteins previously found in exosomes, consistent with the idea that HIV uses the late endosome/multivesicular body pathway during virion budding from macrophages.
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PMID:Proteomic and biochemical analysis of purified human immunodeficiency virus type 1 produced from infected monocyte-derived macrophages. 1694 May 16


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