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)

Peptides derived from measles virus (MV) are presented by MHC class I molecules at widely divergent levels, but it is currently unknown how functional these levels are. Here, for the first time, we studied the natural occurrence and the underlying processing events of a known MV CTL epitope derived from the fusion glycoprotein (MV-F) and restricted via HLA-B*2705. Using MHC-peptide elution of MV-infected cells followed by sensitive mass spectrometry we determined the naturally occurring sequence to be RRYPDAVYL, corresponding to MV-F(438-446). Its level of expression was enumerated at approximately 1500 copies per cell, which is considered to be abundant, but lies within the range described for other viral CTL epitopes in human MHC class I molecules. We found that processing of the MV-F(438-446) epitope occurs primarily via the classic MHC class I loading pathway, since presentation to CTL depends on both the transporter associated with antigen presentation (TAP) and the proteasome. Even though it is cotranslationally inserted into the ER, a major part of MV-F is located in the cytosol, where it accumulates rapidly in the presence of proteasome inhibitors. We therefore conclude that a substantial cytosolic turnover of MV-F, together with some excellent processing features of MV-F(438-446) precursors, such as precise C-terminal excision by proteasomes, efficient TAP transport and strong HLA binding, dictate the abundant functional expression of the MV-F(438-446) CTL epitope in HLA-B*2705 at the surface of MV-infected cells.
J Gen Virol 2001 Sep
PMID:A measles virus glycoprotein-derived human CTL epitope is abundantly presented via the proteasomal-dependent MHC class I processing pathway. 1151 22

The cyclin-dependent kinase inhibitor p27KIP1 plays a key role in controlling cell proliferation. Here we show that p27KIP1 is commonly down-regulated in B-cells immortalized by Epstein-Barr virus (EBV) (lymphoblastoid cell lines, LCLs). The significance of this event for the immortal phenotype of LCLs is implied by a requirement for active cdk2-containing complexes for continued proliferation, and by the ability of the residual p27KIP1 to associate with cdk2. The mechanism of p27KIP1 attenuation is post-translational, but inhibitor studies reveal that the mechanism does not rely heavily on the proteasome. Instead we find that LCLs contain an activity that cleaves a caspase recognition site present in p27KIP1 (DPSD139). The activity is not associated with apoptosis and closely resembles a proliferation-associated caspase activity we previously described in the EBV-negative B-lymphoma-derived cell line BJAB. Importantly, proliferating LCLs contain a p27KIP1 product that is consistent with cleavage at this site. Inhibition of caspase(s) in vivo modulates p27KIP1 expression and strongly inhibits proliferation of IB4 cells. This inhibitor profile is identical to that displayed by the DPSD-directed caspase present in BJAB cells, suggesting that the caspase may fulfil a general role in controlling p27KIP1 expression in immortal lymphoid cell lines. Thus, apoptosis-independent cleavage appears to contribute to the maintenance of the low basal levels of p27KIP1 in B-cells immortalized by EBV.
J Gen Virol 2001 Dec
PMID:Regulation of p27KIP1 in Epstein-Barr virus-immortalized lymphoblastoid cell lines involves non-apoptotic caspase cleavage. 1171 84

The discs large (Dlg) tumour suppressor protein is targeted for ubiquitin-mediated degradation by the high-risk human papillomavirus E6 proteins. To understand further the mechanisms behind this, a mutational analysis of Dlg was undertaken. This study demonstrates that an intact PDZ domain 2 (PDZ2) on Dlg is necessary for the ability of E6 to bind and degrade Dlg. However, additional residues within the amino-terminal portion of Dlg are also required for optimal E6 activity. Stable cell lines expressing different Dlg mutants were also established and these confirm that Dlg is regulated intrinsically by the proteasome in the absence of E6; however, in this case, the sequences responsible for regulating Dlg stability lie predominantly within PDZ2. These results suggest that there are at least two mechanisms for regulating Dlg protein stability and that the pathways used by E6 are not necessarily the same as those used in the cell in its absence.
J Gen Virol 2002 Feb
PMID:Mutational analysis of the discs large tumour suppressor identifies domains responsible for human papillomavirus type 18 E6-mediated degradation. 1180 20

The herpes simplex virus type 1 (HSV-1) mutant d109 does not express any of the immediate-early (IE) proteins and persists in cells for a prolonged length of time. As has been shown by Nicholl et al. (J. Gen. Virol. 81:2215-2218, 2000) and Mossman et al. (J. Virol. 75:750-758, 2001) using other mutants defective for IE gene expression, infection with d109 induced the expression of a number of interferon-stimulated genes. Induction of these genes was significantly greater at multiplicities of infection (MOI) of 10 PFU/cell or greater, and the resulting antiviral effect was only seen at MOIs greater than 10 PFU/cell. Using mutants defective for sets of IE genes established that the lack of ICP0 expression was necessary for high levels of interferon-stimulated gene expression in HEL cells. The induction of interferon-stimulated genes by d109 could also be inhibited by infection with an E1-:E3-:E4- adenovirus expressing levels of ICP0 that are comparable to those expressed within the first hour of wild-type virus infection. Lastly, the addition of the proteasome inhibitor MG132 to cells infected with a mutant that expresses ICP0, d106, also resulted in the induction of interferon-stimulated genes. Thus, ICP0 may function through the proteasome very early in HSV infection to inhibit a cellular antiviral response induced by the virion.
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PMID:Expression of herpes simplex virus ICP0 inhibits the induction of interferon-stimulated genes by viral infection. 1183 95

Tax, the trans-activator of human T-lymphotropic virus type I (HTLV-I), is the dominant target antigen for cytotoxic T lymphocytes (CTLs) in the majority of infected individuals, although the reason for this immunodominance is not clear. Tax has been shown to associate physically with the proteasome, a protease that is responsible for the generation of the majority of major histocompatibility complex (MHC) class I ligands recognized by CTLs. This association could lead to the preferential targeting of Tax to the MHC class I pathway and account for its high immunogenicity. Here, the CTL response to Tax was investigated in mice by priming with a Tax expression vector and boosting with a Tax recombinant vaccinia virus (modified vaccinia virus Ankara strain). This approach led to the identification of a new H-2D(k)-restricted epitope in Tax, amino acid residues 38-46, sequence ARLHRHALL. Surprisingly, presentation of this epitope was found to be enhanced by the proteasome inhibitor lactacystin, although Tax was shown to associate with proteasomes in murine cells. The difficulties encountered in generating Tax-specific CTL responses and the results of enzyme-linked immunospot (ELISpot) analysis suggested that Tax is only poorly immunogenic for CTLs in mice. Therefore, the immunodominance of Tax in human CTL responses to HTLV-I is probably not due to an intrinsic property of the protein itself, such as an association with the proteasome, but instead may result from the fact that Tax is the predominant protein synthesized early after infection.
J Gen Virol 2002 Mar
PMID:Presentation of a new H-2D(k)-restricted epitope in the Tax protein of human T-lymphotropic virus type I is enhanced by the proteasome inhibitor lactacystin. 1184 59

Early during infection, the herpes simplex regulatory protein ICP0 promotes the proteasome-dependent degradation of a number of cellular proteins and the loss of a number of SUMO-1-modified protein isoforms, including PML. Recently, ICP0 has been shown to induce the accumulation of conjugated ubiquitin and function as a ubiquitin E3 ligase. However, certain aspects of the biochemistry, cell biology and the links between SUMO-1 conjugation/deconjugation and protein degradation remain unclear. For example, it is not currently known whether SUMO-1 deconjugation is a prerequisite for ubiquitination or degradation and, if so, by what mechanism this may occur. To help address these questions, a SUMO-specific protease (SENP1) was cloned and its expression and localization in relation to ICP0 examined. A cell line was established which constitutively expresses SUMO-1 to facilitate studies of localization and biochemistry. SENP1 localized to the nucleus mainly in discrete subdomains, a subset of which co-localized with the PML bodies. Both ICP0 and SENP1 protease promoted the loss of SUMO-1 from the nucleus, observed both for the endogenous species and the cell line expressing the epitope-tagged SUMO-1. The tagged SUMO-1 was recruited into high molecular mass conjugates in the cell line, and expression of SENP1 promoted loss of these species, including the modified species of PML. Finally, in co-transfection experiments ICP0 promoted the recruitment of SENP1 to nuclear domains, a result which was also observed early during infection. The significance of these findings is discussed in relation to the function of ICP0.
J Gen Virol 2002 Dec
PMID:Herpes simplex virus 1 ICP0 co-localizes with a SUMO-specific protease. 1246 71

Plant viruses move to adjacent cells with the use of virus-encoded cell-to-cell movement proteins. Using proteins produced by in vitro translation, we present evidence that the '69K' movement protein of Turnip yellow mosaic virus (TYMV) is recognized as a substrate for the attachment of polyubiquitin chains and for subsequent rapid and selective proteolysis by the proteasome, the ATP-dependent proteolytic system present in reticulocyte lysate. Truncation of the 69K protein suggests the existence of two degradation signals within its sequence. We propose that selective degradation of virus movement proteins may contribute to the previously reported transient nature of their accumulation during infection.
J Gen Virol 2002 Dec
PMID:Stability in vitro of the 69K movement protein of Turnip yellow mosaic virus is regulated by the ubiquitin-mediated proteasome pathway. 1246 97

The production of alkaline protease of Aspergillus oryzae U1521 was examined in liquid culture. In a culture of defatted soybean only, it gave satisfactory enzyme yields at 584,000 U/g defatted soybean. When various carbohydrates were supplemented, enzyme production was significantly increased. An increase in production by lactose was the most marked. Enrichment with casitone or casein increased productivity, but not cornsteep solid. Media formulation (g/L) of defatted soybean 10, lactose 5, casitone 1, and KH(2)PO(4) 5 enhanced alkaline protease production by A. oryzae U1521 to a maximum of 1,410,000 U/g defatted soybean. Scaling-up experiments indicated the flask-scale results could be reproduced at 40 g of substrate in 5-L fermenter. The enzyme activity was maximum between pH 8-9 and at a temperature of 45 degrees C.
J Gen Appl Microbiol 1999 Jun
PMID:Production of alkaline protease by a genetically engineered Aspergillus oryzae U1521. 1250 79

Human T-cell leukaemia virus type 1 (HTLV-I), the aetiological agent of adult T-cell leukaemia (ATL) and tropical spastic paraparesis (TSP/HAM), transforms human T-cells in vivo and in vitro. The Tax protein of HTLV-I is essential for cellular transformation as well as viral and cellular gene transactivation. The interaction of Tax with cellular proteins is critical for these functions. We previously isolated and characterized a novel Tax-binding protein, TRX (TAX1BP2), by screening a Jurkat T-cell cDNA library. In the present study, we present evidence that the tumour suppressor p53 targets the TRX protein for proteasome degradation. Pulse-chase experiments revealed that p53 enhanced the degradation of TRX protein and reduced the half-life from 2.0 to 0.25 h. p53 mutants R248W and R273H enhance TRX degradation suggesting a transcriptionally independent mechanism. Both HTLV-I Tax and the proteasome-specific inhibitor MG132 inhibited p53-mediated TRX protein degradation. These results suggest that TRX degradation is mediated through activation of the proteasome protein degradation pathway independent of transcriptional function of p53. Our results provide the first experimental evidence that Tax inhibits transcription-dependent and independent functions of p53.
J Gen Virol 2003 Apr
PMID:P53 facilitates degradation of human T-cell leukaemia virus type I Tax-binding protein through a proteasome-dependent pathway. 1265 90

Human papillomaviruses (HPVs) are aetiological agents for genital warts and cervical cancer, the different pathologies of which are dependent on the type of HPV infection. Oncogenic HPV types associated with cancer are carcinogens by virtue of their oncogene products, which target key regulators of cell proliferation and apoptosis. The viral E6 protein from oncogenic HPV types plays a central role in carcinogenesis by exploiting the cellular proteasome degradation pathway in order to mediate the degradation of cellular proteins, most notably the prototype tumour suppressor protein p53. Much less is known about the cellular targets of E6 from the non-oncogenic HPV types associated with genital warts. It is also unclear what factors influence the level and stability of the viral E6 proteins in cells. This report demonstrates that both oncogenic and non-oncogenic HPV E6 proteins (from types 18 and 11, respectively) are ubiquitinated and targeted for degradation by the 26S proteasome. E6 domains required for the induction of p53 or DLG degradation, or E6AP binding, are not involved in proteasome-mediated degradation of HPV-18 E6. These results provide insight into the cellular modulation of E6 protein levels from both high-risk and low-risk HPV types.
J Gen Virol 2004 Jun
PMID:Ubiquitination and proteasome degradation of the E6 proteins of human papillomavirus types 11 and 18. 1516 24


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