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)

The papain superfamily member bleomycin hydrolase (Blmh) is a neutral cysteine protease with structural similarity to a 20S proteasome. Bleomycin (BLM), a clinically used glycopeptide anticancer agent, is deaminated in vitro by Blmh. We used gene targeting to generate mice that lack Blmh and demonstrated that Blmh is the sole enzyme required for BLM deamination. Although some Blmh null mice were viable and reproduced, only about 65% of the expected number survived the neonatal period, revealing an important role for Blmh in neonatal survival. Mice lacking Blmh exhibited variably penetrant tail dermatitis that resembled rodent ringtail. The histopathology of the tail dermatitis was similar to skin lesions in humans with pellagra, necrolytic migratory erythema, and acrodermatitis enteropathica. Compared with controls, Blmh null mice were more sensitive to acute BLM lethality and developed pulmonary fibrosis more readily following BLM treatment. Thus, we have established that Blmh is an essential protectant against BLM-induced death and has an important role in neonatal survival and in maintaining epidermal integrity.
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PMID:The neutral cysteine protease bleomycin hydrolase is essential for epidermal integrity and bleomycin resistance. 1020 Mar 22

Bleomycin hydrolase (BH) is a cysteine proteinase that inactivates the anticancer drug bleomycin. Yeast BH forms a homohexameric structure that resembles a 20S proteasome and binds to single-stranded RNA and DNA. We now demonstrate that human BH (hBH) interacts and colocalizes with ribosomal proteins. Using a yeast two-hybrid system, we found hBH bound to human homologues of rat ribosomal proteins L11 and L29. The N-terminus of hBH (amino acids 14-175), which contains a catalytic Cys93, was critical for the binding to L11 in the two-hybrid environment. hBH precipitated 35S-labeled L11 and L29 in vitro, and hBH colocalized with L11 and L29 as determined by immunofluorescence. In addition to cytosolic bleomycin hydrolase, we found abundant bleomycin hydrolase activity associated with the ribosomal subcellular fraction by differential centrifugation. hBH was also detected by Western immunoblotting in a high-speed particulate fraction, where the majority of L11 and L29 were found. In vitro experiments showed recombinant hBH binds to Chinese hamster ovary cell microsomes. Thus, our data strongly suggest that hBH exists as both a free cytosolic and ribosome-associated protein.
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PMID:Human bleomycin hydrolase binds ribosomal proteins. 1035 21

The proteasome generates exact major histocompatibility complex (MHC) class I ligands as well as NH2-terminal-extended precursor peptides. The proteases responsible for the final NH2-terminal trimming of the precursor peptides had, until now, not been determined. By using specific selective criteria we purified two cytosolic proteolytic activities, puromycin-sensitive aminopeptidase and bleomycin hydrolase. These proteases could remove NH2-terminal amino acids from the vesicular stomatitis virus nucleoprotein cytotoxic T cell epitope 52-59 (RGYVYQGL) resulting, in combination with proteasomes, in the generation of the correct epitope. Our data provide evidence for the existence of redundant systems acting downstream of the proteasome in the antigen-processing pathway for MHC class I molecules.
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PMID:Two new proteases in the MHC class I processing pathway. 1106 1

The proteasome is now recognized to be implicated in the generation of the vast majority of MHC class I ligands. Moreover, it is probably the only cytosolic protease generating their carboxyterminals. However, solid evidence documents a role of additional and only partly identified proteases in MHC class I antigen processing. Cytosolic tripeptidyl peptidase (TTP II) may be able to carry out some functions normally ascribed to the proteasome, including that of generating antigenic peptides. Several cytosolic enzymes, including bleomycin hydrolase (BH) and puromycin-sensitive aminopeptidase (PSA), but especially the IFNgamma-inducible leucyl aminopeptidase (LAP), can trim the aminoterminal ends of class I ligands. The vast majority of cytosolic peptides is degraded, a process likely to limit antigen presentation, in which thimet oligopeptidase (TOP) may play an important role. Proteolytic activity in the secretory pathway, though much more limited than in the cytosol, also contributes to class I antigen presentation. Signal peptide fragments and peptides at the carboxyterminal end of various proteins targeted to the endoplasmic reticulum can be highly efficient TAP-independent class I ligands. However, an as yet unidentified luminal trimming aminopeptidase may eventually turn out to play the most important role for class I ligand generation in the secretory pathway. Defining the extent of the involvement of cytosolic and luminal peptidases in class I antigen processing will be a challenging task for the future.
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PMID:Beyond the proteasome: trimming, degradation and generation of MHC class I ligands by auxiliary proteases. 1220 51

MHC-class-I-presented peptides are predominantly generated by the proteasome system. IFN-gamma strongly influences the processing efficiency by inducing immunoproteasome formation and proteasome activator PA28 synthesis. Depending on the protein substrate, the presence of immunoproteasomes and PA28 influence epitope liberation either positively or negatively. Abundantly occurring defective ribosomal products are a major source for proteasome-dependent antigen processing; however, antigen presentation is relatively inefficient. This is in part due to the existence of a panel of cytosolic aminopeptidases, such as bleomycin hydrolase (BH), puromycin-sensitive aminopeptidase (PSA) and thimet oligoendopeptidase (TOP), that can destroy epitopes or their precursors. Other aminopeptidases, such as leucine aminopeptidase (LAP) and endoplasmic reticulum aminopeptidase 1 (ERAP 1), can trim epitope precursors from the amino terminus to their correct size for MHC class I binding to enhance antigen presentation. Recent evidence suggests that tripeptidyl peptidase II (TPPII), a large peptidase with exo-and endo-proteolytic activities, is also involved in antigen processing and may generate a specific set of MHC class I epitopes.
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PMID:Proteasome and peptidase function in MHC-class-I-mediated antigen presentation. 1473 13

Antigenic peptides presented to major histocompatibility complex (MHC) class I molecules are generated in the cytosol during degradation of cellular proteins by the ubiquitin-proteasome proteolytic pathway. Proteasome can generate N-extended precursors as well as final epitopes, and then the precursors are processed to mature epitopes by aminopeptidases. Both cytosolic peptidases (i.e. puromycin-sensitive aminopeptidase, bleomycin hydrolase and interferon-gamma-inducible leucine aminopeptidase) and recently identified metallo-aminopeptidase located in the endoplasmic reticulum (i.e. adipocyte-derived leucine aminopeptidase/endoplasmic reticulum aminopeptidase 1 and leukocyte-derived arginine aminopeptidase) can generate final epitopes from precursor peptides. Some of these aminopeptidases are also considered to destroy certain antigenic peptides to limit the antigen presentation. Taken together, it is getting evident that aminopeptidases located in the cytosol and the lumen of endoplasmic reticulum play important roles in the generation of antigenic peptides presented to MHC class I molecules.
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PMID:Processing of antigenic peptides by aminopeptidases. 1518 16

The proteasome is primarily responsible for the generation of MHC class I-restricted CTL epitopes. However, some epitopes, such as NP(147-155) of the influenza nucleoprotein (NP), are presented efficiently in the presence of proteasome inhibitors. The pathways used to generate such apparently "proteasome-independent" epitopes remain poorly defined. We have examined the generation of NP(147-155) and a second proteasome-dependent NP epitope, NP(50-57), using cells adapted to growth in the presence of proteasome inhibitors and also through protease overexpression. We observed that: 1) Ag processing and presentation proceeds in proteasome-inhibitor adapted cells but may become more dependent, at least in part, on nonproteasomal protease(s), 2) tripeptidyl peptidase II does not substitute for the proteasome in the generation of NP(147-155), 3) overexpression of leucine aminopeptidase, thymet oligopeptidase, puromycin-sensitive aminopeptidase, and bleomycin hydrolase, has little impact on the processing and presentation of NP(50-57) or NP(147-155), and 4) proteasome-inhibitor treatment altered the specificity of substrate cleavage by the proteasome using cell-free digests favoring NP(147-155) epitope preservation. Based on these results, we propose a central role for the proteasome in epitope generation even in the presence of proteasome inhibitors, although such inhibitors will likely alter cleavage patterns and may increase the dependence of the processing pathway on postproteasomal enzymes.
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PMID:Re-evaluating the generation of a "proteasome-independent" MHC class I-restricted CD8 T cell epitope. 1645 81

Antigenic peptides presented by MHC class I molecules are generated mainly by the proteasome in the cytosol. Several cytosolic aminopeptidases further trim proteasomal products to form mature epitopes or individual amino acids. However, the distinct function of cytosolic aminopeptidases in MHC class I Ag processing remains to be elucidated. In this study, we show that cytosolic aminopeptidases differentially affect the cell surface expression of MHC class I molecules in an allele-dependent manner in human cells. In HeLa cells, knockdown of puromycin-sensitive aminopeptidase (PSA) by RNA interference inhibited optimal peptide loading of MHC class I molecules, and their cell surface expression was correspondingly reduced. In contrast, depletion of bleomycin hydrolase (BH) enhanced optimal peptide loading and cell surface expression of MHC class I molecules. We did not find evidence on the effect of leucine aminopeptidase knockdown on the MHC class I Ag presentation. Moreover, we demonstrated that PSA and BH influence the peptide loading and surface expression of MHC class I in an allele-specific manner. In the absence of either PSA or BH, the surface expression and peptide-dependent stability of HLA-A68 were reduced, whereas those of HLA-B15 were enhanced. The surface expression and peptide-dependent stability of HLA-A3 were enhanced by BH knockdown, although those of HLA-B8 were increased in PSA-depleted conditions.
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PMID:Cytosolic aminopeptidases influence MHC class I-mediated antigen presentation in an allele-dependent manner. 1991 96

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