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)

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

Retroviral late domains (L domains) are short amino acid sequences in the Gag protein that facilitate the process of budding. L domains act by recruiting the ESCRT complexes, which normally function in the formation of multivesicular bodies. The PTAP late domain of human immunodeficiency virus (HIV) is believed to specifically recruit this machinery by binding the ESCRT protein TSG101. It was recently demonstrated that expression of a C-terminal fragment of TSG101 (TSG-3') blocked the budding of both PTAP-dependent and PPPY-dependent retroviruses. We show here that TSG-3' expression leads to the formation of large spherical entities that we call TICS (TSG-3'-induced cellular structures) in the cytoplasm. Rous sarcoma virus (RSV) and murine leukemia virus (MLV) Gag proteins are selectively recruited to these structures, but HIV type 1 Gag is completely excluded. Experiments with various HIV and RSV vector constructs as well as HIV and RSV chimeras suggest that recruitment to the TICS is late domain independent and does not involve recognition of any single amino acid sequence. TICS appear to have no limiting membrane and do not colocalize with markers for any membranous cellular compartment. Wild-type TSG101 is also recruited to TICS, but most other ESCRT proteins are excluded. These structures are similar in nature to aggresomes, colocalize with the aggresome marker GFP-250, and are highly enriched in ubiquitin but in other ways do not fully meet the description of aggresomes. We conclude that the block to retroviral budding by TSG-3' may be the result of its sequestration of Gag, depletion of free TSG101, or depletion of free ubiquitin.
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PMID:The C-terminal half of TSG101 blocks Rous sarcoma virus budding and sequesters Gag into unique nonendosomal structures. 1573 Dec 71

The human immunodeficiency virus type 1 (HIV-1) virion infectivity factor (Vif) overcomes the antiviral activity of APOBEC3G to protect HIV-1 DNA from G-to-A hypermutation. Vif targets APOBEC3G for ubiquitination and proteasomal degradation by forming an SCF-like E3 ubiquitin ligase complex composed of Cullin5, Elongin B, and Elongin C (Vif-BC-Cul5) through a novel SOCS-box motif. In this paper, we have established an in vitro ubiquitin conjugation assay with purified Vif-BC-Cul5 complex and reported that the Vif-BC-Cul5 complex could function as an E3 ligase for APOBEC3G in vitro. A Vif-BC-Cul5 complex promotes the in vitro ubiquitination of the wild type, APOBEC3G but not that of D128K mutant, which does not interact with Vif. We have also investigated several loss-of-function Vif mutants. One mutant, SLQ144/146AAA, lost its activity on APOBEC3G because it could not form a complex due to mutations in SOCS-box motif. Other mutants, C114S and C133S, also lost their activity because of loss of the E3 ligase activity of a Vif-BC-Cul5 complex, although these mutants retained the ability to bind to APOBEC3G as well as Cul5 complex. These findings suggest that the E3 ubiquitin ligase activity of the Vif-BC-Cul5 complex is essential for Vif function against APOBEC3G.
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PMID:Ubiquitination of APOBEC3G by an HIV-1 Vif-Cullin5-Elongin B-Elongin C complex is essential for Vif function. 1578 49

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

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

p27Kip1 that regulates the G1/S transition of cell cycle and inhibits Rho A signaling is frequently lost in several cancers leading to the deregulation of cell growth and cell motility. Mitogen-activated protein kinases (MAPK) regulate the export of p27Kip1 from nucleus to cytoplasm, followed by the degradation with proteases. Skp-2, a subunit of an SCF ubiquitin-protein ligase complex responsible for the ubiquitination of p27Kip1, is upregulated frequently in several cancers, leading to the decrease of p27Kip1. We applied human immunodeficiency virus (HIV) lentivirus-mediated RNA interference (RNAi) to melanoma cells with the BRAF mutation (V599E) and overexpressed Skp-2 and found that the simultaneous suppression of these activated oncogenes resulted in the effective inhibition of in vitro cell growth and invasive ability of melanoma cells accompanied by the additional increase of p27Kip1. Our results suggest that gene therapy against melanoma with the enhanced MAPK and ubiquitin-proteasomal pathways could be a specific and effective therapeutic strategy for cancers.
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PMID:Effective inhibition of cell growth and invasion of melanoma by combined suppression of BRAF (V599E) and Skp2 with lentiviral RNAi. 1605 31

A subset of proteins targeted by the N-end rule pathway bear degradation signals called N-degrons, whose determinants include destabilizing N-terminal residues. Our previous work identified mouse UBR1 and UBR2 as E3 ubiquitin ligases that recognize N-degrons. Such E3s are called N-recognins. We report here that while double-mutant UBR1(-/-) UBR2(-/-) mice die as early embryos, the rescued UBR1(-/-) UBR2(-/-) fibroblasts still retain the N-end rule pathway, albeit of lower activity than that of wild-type fibroblasts. An affinity assay for proteins that bind to destabilizing N-terminal residues has identified, in addition to UBR1 and UBR2, a huge (570 kDa) mouse protein, termed UBR4, and also the 300-kDa UBR5, a previously characterized mammalian E3 known as EDD/hHYD. UBR1, UBR2, UBR4, and UBR5 shared a approximately 70-amino-acid zinc finger-like domain termed the UBR box. The mammalian genome encodes at least seven UBR box-containing proteins, which we propose to call UBR1 to UBR7. UBR1(-/-) UBR2(-/-) fibroblasts that have been made deficient in UBR4 as well (through RNA interference) were significantly impaired in the degradation of N-end rule substrates such as the Sindbis virus RNA polymerase nsP4 (bearing N-terminal Tyr) and the human immunodeficiency virus type 1 integrase (bearing N-terminal Phe). Our results establish the UBR box family as a unique class of E3 proteins that recognize N-degrons or structurally related determinants for ubiquitin-dependent proteolysis and perhaps other processes as well.
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PMID:A family of mammalian E3 ubiquitin ligases that contain the UBR box motif and recognize N-degrons. 1605 22

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.
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PMID:HIV-1 Vif: HIV's weapon against the cellular defense factor APOBEC3G. 1625 Aug 85

Host cell factors modulate retroviral infections. Among those, cyclophilin A (CypA) promotes virus infectivity by facilitating virus uncoating or capsid unfolding or by preventing retroviral capsid interaction with cellular restriction factors. In Aotus species, a retrotransposed copy of CypA inserted into the tripartite motif 5 (TRIM5) gene encodes a fusion protein which may block human immunodeficiency virus type 1 by targeting the incoming virus to ubiquitin-ligated degradation or by interfering with normal uncoating of the incoming particle, rendering those monkeys resistant to infection. In this study, we have extensively analyzed representative specimens from all New World primate genera and shown that the retrotransposed CypA copy is only present in Aotus. We have shown that this inserted copy diverged from its original counterpart and that this occurred prior to Aotus radiation, although no positive selection was observed. Finally, our data underscores the need for a precise taxonomic identification of primate species used as models for retroviral infections and novel antiviral approaches.
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PMID:Evolution of cyclophilin A and TRIMCyp retrotransposition in New World primates. 1628 2

TRIM-CypA is an owl monkey-specific variant of the retrovirus restriction factor TRIM5alpha. Here, we exploit its modular domain organization and cyclosporine sensitivity to probe the kinetics and mechanism of TRIM5-mediated restriction. Time of addition/withdrawal experiments reveal that inhibition of incoming human immunodeficiency virus type 1 capsids by TRIM-CypA occurs within minutes of their delivery to the target cell cytoplasm. However, while TRIM-CypA restriction is partly dependent on a RING domain, restriction occurs independently of the ubiquitin/proteasome system. Moreover, tagged TRIM-CypA proteins can be fully active as restriction factors without forming cytoplasmic bodies.
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PMID:Restriction of human immunodeficiency virus type 1 by TRIM-CypA occurs with rapid kinetics and independently of cytoplasmic bodies, ubiquitin, and proteasome activity. 1630 27


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