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)

Proteasomes catalyze the non-lysosomal, ATP-dependent selective breakdown of ubiquitinated proteins and are thought to be responsible for MHC class I-restricted antigen presentation. Recently, we reported that gamma interferon (IFN-gamma) induced not only marked synthesis of the MHC-encoded proteasome subunits LMP2 and LMP7, but also almost complete loss of two unidentified proteasome subunits tentatively designated as X and Y in various human cells. Here, we show that subunit X is a new proteasomal subunit highly homologous to LMP7, and that subunit Y is identical to the LMP2-related proteasomal subunit delta. Thus, IFN-gamma appears to induce subunit replacements of X and Y by LMP7 and LMP2, respectively, producing 'immuno-proteasomes' with the functional diversity responsible for processing of endogenous antigens.
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PMID:Replacement of proteasome subunits X and Y by LMP7 and LMP2 induced by interferon-gamma for acquirement of the functional diversity responsible for antigen processing. 816 24

To obtain information on the role of proteasomes in the immune system, we examined the effect of a major immunomodulatory cytokine, gamma interferon (IFN-gamma), on the expressions, structures, and functions of proteasomes. IFN-gamma greatly increased the levels of the mRNAs encoding LMP2 and LMP7, putative immuno-proteasome subunits encoded by genes within the class II MHC region, and these two subunits synthesized were assembled completely into the proteasomal multi-subunit complex in various types of human cells. The subunit organization of proteasome changed in response to IFN-gamma stimulation, due to assembly of newly synthesized subunits through up- and down-expressions of at least 6 proteasome genes including LMP2/LMP7 without change in the structure of pre-existing proteasomes. Interestingly, IFN-gamma dramatically stimulated the trypsin-like and chymotrypsin-like activities of the multifunctional proteasome and depressed the peptidylglutamyl-peptide-hydrolyzing activity, without affecting the activity for ATP-, ubiquitin-dependent proteolysis. These results indicate that IFN-gamma modifies not only the structural organization of the proteasome, but also its functions. Based on these findings, we discuss the role in the antigen processing/presentation pathway of proteasomes with functional diversity acquired through alteration of their subunit assembly in response to IFN-gamma stimulation.
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PMID:Interferon-gamma induces different subunit organizations and functional diversity of proteasomes. 820 75

The processing pathway for the MHC class II-restricted presentation of endogenous cytosolic Ag is distinct from the class I pathway since a cytosolic form of the influenza virus A hemagglutinin, expressed by a recombinant vaccinia virus, was presented by HLA-DR in a B cell mutant lacking the TAP1 subunit of the transporter for Ag presentation (TAP). In this report, two additional B cell mutants have been used to define the requirements of this TAP1-independent processing pathway. The first mutant, .61, lacks expression of both TAP1 and TAP2 genes, and of both LMP2 and LMP7 genes encoding proteasome subunits. As expected, class I-restricted presentation of the influenza virus matrix protein was totally deficient in mutant .61. In contrast, class II-restricted presentation of both the natural cytosolic matrix and the engineered cytosolic hemagglutinin proteins was functional in mutant .61. Thus, presentation of cytosolic Ag by class II molecules is independent of both TAP subunits and of the two MHC-encoded proteasome subunits. However, this endogenous processing pathway is dependent on at least one other function encoded in the class II region of the MHC as demonstrated with the second mutant, .174, in which a large deletion eliminates all expressed class II genes. Mutant .174 transfected with HLA-DR1 genes was previously shown to be defective in the presentation of exogenous Ag but normal in the presentation of short exogenous peptides. We show here that .174(DR1) is also defective in the presentation of cytosolic matrix and hemagglutinin proteins. This similar requirement for the class II-restricted presentation of either cytosolic Ag or internalized exogenous Ag suggests that both forms of Ag are ultimately targeted to the same cellular compartment for association with class II molecules.
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PMID:Presentation of cytosolic antigen by HLA-DR requires a function encoded in the class II region of the MHC. 825 89

The products of the Lmp2 and Lmp7 genes located in the major histocompatibility complex (MHC) class II region are postulated to form part of the proteasome complex. This large, multisubunit complex forms the major, nonlysosomal proteolytic machinery for the degradation of endogenous proteins and has been suggested to play a role in the processing of antigens presented by MHC class I molecules. The role of the MHC-encoded subunits within the proteasome has however remained enigmatic. To study this role, we have raised antibodies to recombinant LMP2 and LMP7 proteins. Under denaturing conditions, the anti-LMP7 serum recognizes one subunit of proteasome, whereas the anti-LMP2 serum recognizes two subunits, which may represent different forms of LMP2. The specificity of these sera has been ascertained by a lack of reactivity in T2 cells, which lack both genes. Furthermore under native conditions the anti-LMP2 serum immunoprecipitates a complex that is similar to proteasome but lacks several subunits, including LMP7. Preclearing experiments using this serum and a monoclonal antibody (2-17) specific for the non-MHC-encoded C2 proteasome subunit demonstrate that the complexes recognized by these two sera are distinct and that four subunits are unique to the complex precipitated by the anti-LMP2 serum. Interestingly, the different forms of LMP2 are segregated between these complexes. The relationship of the two complexes is discussed.
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PMID:Delineation of the subunit composition of human proteasomes using antisera against the major histocompatibility complex-encoded LMP2 and LMP7 subunits. 827 81

The mouse Lmp-2 gene is located within the major histocompatibility complex (MHC) class II region and encodes a subunit of the 20S cytosolic proteasome. Previous studies indicated that the 20S proteasome is a catalytic core of the 26S proteolytic complex that possesses a latent multicatalytic proteinase activity and catalyzes an ATP-dependent, selective breakdown of proteins ligated to ubiquitin. This complex has recently been postulated to be involved in the processing of endogenous antigenic peptides for the MHC class I pathway. Here, we report the genomic organization and tissue expression of the mouse Lmp-2 gene. We have cloned and sequenced the entire mouse Lmp-2 gene, including 5'- and 3'-flanking regions. The gene consists of six exons, and its genomic organization is very similar to that of the recently described human LMP2 gene. Putative promoter and enhancer elements were identified in the 5'-flanking region by sequence comparison with known consensus sequences. The Lmp-2 gene is expressed in most tissues of unstimulated mice, except for brain tissue. The comparison of the 5'-flanking region of human and mouse sequences is discussed.
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PMID:Genomic organization and tissue expression of mouse proteasome gene Lmp-2. 832 39

Proteasomes are 650-kDa, multisubunit endopeptidases that might be involved in the MHC class I Ag processing pathway. We demonstrate the existence of multiple structurally distinct subsets of proteasomes. Distinct forms of proteasomes share a hypothetical core to which unique subunits are added. One of these subsets, LMP2+ proteasome, contains the product of the MHC-linked Lmp-2 gene, and can be distinguished serologically and structurally from other proteasome subsets. The expression of LMP2+ and LMP2- proteasomes is variable among cell lines of different tissue types, and their relative abundance and subunit composition are regulated by IFN-gamma. LMP2+ proteasomes comprise 0 to 74% of total cellular proteasomes. Both LMP2+ and LMP2- proteasomes are proteolytically active. We suggest proteasome function might be regulated by subunit composition, and some, or all proteasome subsets, might participate in the production or delivery of peptides to MHC class I molecules. Both LMP2+ and LMP2- subsets can be further subdivided on the basis of the presence or absence of other unique subunits. Implications of the existence of structurally distinct forms of proteasomes in different tissue types is discussed.
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PMID:MHC-linked low-molecular mass polypeptide subunits define distinct subsets of proteasomes. Implications for divergent function among distinct proteasome subsets. 833 24

The proteasome (high-molecular-mass multicatalytic proteinase complex) is composed of a large number of non-identical protein subunits of the alpha and beta types. The mouse beta-type subunits LMP2 and LMP7 (LMP, low-molecular-mass protein) are encoded within the mouse major histocompatibility complex (MHC II) region, and are thought to connect the proteasome to the MHC class-I antigen-processing pathway. In the present communication, we have analysed the two proteasome subunits with regard to their identity within the proteasome complex, their protein levels, their amounts of mRNA in different mouse tissues and cell lines, and have investigated the intracellular localization of LMP2 and LMP7 subunits in thymus and liver by immunocytology. Our experiments indicate that LMP2 and LMP7 subunits are synthesized as precursor proteins of 24 kDa and 30 kDa, respectively, and that only the processed 21-kDa and 23-kDa subunits are part of the 20S proteasome complex. The proportion of LMP2-subunit-containing and LMP7-subunit-containing proteasome complexes, as well as LMP2 and LMP7 mRNA levels, vary strongly and are shown to be dependent on the tissues or cell lines analysed. Furthermore, high LMP2 and LMP7 mRNA levels do not always correlate with high protein levels, suggesting a specific translational mechanism which controls proteasome subunit synthesis. Generally, mRNA levels appear to be particularly high in those tissues which are known to be involved in MHC class-I antigen presentation. Immunocytological analysis shows a strong nuclear localization of the subunits in cells of the thymus, while in the liver they appear to be evenly distributed between the two cellular compartments. Our data support the idea that both LMP2 and LMP7 proteins are non-essential proteasome subunits which are probably involved in the regulation of proteasome activities. The function of the two subunits, however, may not be restricted to the proposed role of proteasomes in antigen presentation.
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PMID:The major-histocompatibility-complex-encoded beta-type proteasome subunits LMP2 and LMP7. Evidence that LMP2 and LMP7 are synthesized as proproteins and that cellular levels of both mRNA and LMP-containing 20S proteasomes are differentially regulated. 836 98

Proteasomes are highly conserved macromolecular structures which function as endopeptidases. They are found in the cytoplasm and nucleus of eukaryotic tissues and consist of at least 14 non-identical subunits with molecular masses ranging from approximately 20 to 32K. Proteasomes are essential in the selective degradation of ubiquitinated and certain non-ubiquitinated proteins, acting as the proteolytic core of an energy-dependent 26S (1,500K) proteolytic complex. Two proteasome subunits, LMP2 and LMP7 (refs 4-7), are encoded within the major histocompatibility complex (MHC), implicating proteasomes in antigen processing. Here we determine the function of these two MHC-linked subunits by comparing the proteolytic activities of purified proteasomes containing (LMP+) or lacking (LMP-) these components. We find that proteasomes of both types have endopeptidase activity against substrates bearing hydrophobic, basic or acidic residues immediately preceding the cleavage site (the P1 position) and at sites following asparagine, glycine and proline residues. The activity of LMP+ proteasomes is much higher than that of LMP- proteasomes against substrates with hydrophobic, basic or asparagine residues at P1, whereas their activities are comparable when acidic and glycine residues are present at P1. The MHC-linked LMP2 and LMP7 subunits therefore function to amplify specific endopeptidase activities of the proteasome.
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PMID:MHC-linked LMP gene products specifically alter peptidase activities of the proteasome. 837 76

The presentation of intracellular proteins to the immune system requires their degradation to small peptides that then become associated with major histocompatibility complex (MHC) class I molecules. The generation of these peptides may involve the 20S or 26S proteasome particles, which contain multiple proteolytic activities including distinct sites that preferentially cleave small peptides on the carboxyl side of hydrophobic, basic or acidic residues. Degradation of most cell proteins requires their conjugation to ubiquitin before hydrolysis by the 26S proteasome. This large complex contains the 20S proteasome as its proteolytic core. This ubiquitin-dependent proteolytic pathway is implicated in MHC class I presentation. gamma-Interferon (gamma-IFN), a stimulator of antigen presentation, induces a subclass of proteasomes that contain two MHC-encoded subunits, LMP2 and 7 (refs 5-10). Here we show that gamma-interferon alters the peptidase activities of the 20S and 26S proteasomes without affecting the rates of breakdown of proteins or of ubiquitinated proteins. By enhancing the expression of MHC genes, gamma-IFN increases the proteasomes' capacity to cleave small peptides after hydrophobic and basic residues but reduces cleavage after acidic residues. Moreover, proteasomes of mutants lacking LMP subunits show decreased rates of cleavage after hydrophobic and basic residues. Thus, gamma-IFN and expression of these MHC genes should favour the production by proteasomes of the types of peptides found on MHC class I molecules, which terminate almost exclusively with hydrophobic or basic residues.
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PMID:Gamma-interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes. 837 76

The 20S proteasome is a protease complex of functional importance for antigen processing. Two of the 14 proteasome subunits, delta and MB1, can be replaced by the major histocompatibility complex (MHC)-encoded and interferon-gamma (IFN-gamma)-inducible subunits LMP2 and LMP7, respectively. LMP2 and LMP7 alter the cleavage site specificity of the 20S proteasome and are required for the efficient generation of T cell epitopes from a number of viral proteins and for optimal MHC class I cell surface expression. We compared the 20S proteasome subunit pattern from IFN-gamma-induced and non-induced mouse fibroblasts on two-dimensional gels and identified a third subunit exchange by microsequencing: the non-MHC-encoded subunit MECL-1 is induced by IFN-gamma and replaces a sofar barely characterized beta subunit designated 'MC14'. In analogy to LMP2 and LMP7, MECL-1 may be functional in MHC class I-restricted antigen presentation.
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PMID:A third interferon-gamma-induced subunit exchange in the 20S proteasome. 862 80


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