Identification of 33 polymorphisms in the adipocyte-derived leucine aminopeptidase (ALAP) gene and possible association with hypertension

Yamamoto, Nao; Nakayama, Junko; Yamakawa‐Kobayashi, Kimiko; Hamaguchi, Hideo; Miyazaki, Ryunosuke; Arinami, Tadao

doi:10.1002/humu.10047

Cited by 90 publications

(88 citation statements)

References 13 publications

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“…5) and the resulting specificity for 9-to 16-residue substrates, like its subcellular localization and regulation by IFN-␥, must have evolved to facilitate immune surveillance. Much, however, remains to be learned about its precise role in processing different types of epitopes, the possible immunological significance of the human polymorphisms in ERAP1 (46), and the structural basis for its molecular ruler mechanism.…”

Section: Discussionmentioning

confidence: 99%

The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism

Chang

Momburg

Bhutani

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

300

336

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Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an IFN-␥-induced aminopeptidase in the endoplasmic reticulum that trims longer precursors to the antigenic peptides presented on MHC class I molecules. We recently reported that purified ERAP1 trimmed N-extended precursors but spared peptides of 8 -9 residues, the length required for binding to MHC class I molecules. Here, we show another remarkable property of ERAP1: that it strongly prefers substrates 9 -16 residues long, the lengths of peptides transported efficiently into the ER by the transporter associated with antigen processing (TAP) transporter. This aminopeptidase rapidly degraded a model 13-mer to a 9-mer and then stopped, even though the substrate and the product had identical N-and C-terminal sequences. No other aminopeptidase, including the closely related ER-aminopeptidase ERAP2, showed a similar length preference. Unlike other aminopeptidases, the activity of ERAP1 depended on the C-terminal residue of the substrate. ERAP1, like most MHC class I molecules, prefers peptides with hydrophobic C termini and shows low affinity for peptides with charged C termini. Thus, ERAP1 is specialized to process precursors transported by TAP to peptides that can serve as MHC class I epitopes. Its ''molecular ruler'' mechanism involves binding the hydrophobic C terminus of the substrate 9 -16 residues away from the active site.antigen presentation ͉ antigen processing ͉ proteases M HC class I molecules bind tightly and display on the cell surface antigenic peptides that are derived from peptides generated during the degradation of intracellular proteins. If nonnative peptides (e.g., from viral proteins) are presented, they are recognized by circulating cytotoxic T lymphocytes (1-4). To fit in the groove in most MHC class I molecules, these antigenic peptides must have a length of 8-10 residues (5, 6), although certain class I molecules can admit peptides up to 11 residues (7). It is now firmly established that the proteasome pathway is responsible for the generation of the great majority of antigenic peptides (8-10). Proteasomes generally degrade proteins to peptide fragments ranging from 2-25 residues long (11), but most are too short (Ͻ8 residues) for antigen presentation. Several studies using proteasome inhibitors have further shown that cleavages within proteasomes define the C-terminal residues of MHC class I-presented peptides (12). However, their N termini often are generated by aminopeptidases, which trim longer N-extended proteasome products to the mature epitopes (13). In fact, proteasomes, and especially immunoproteasomes (1), the forms found in immune tissues and induced by IFN-␥ elsewhere, seem to preferentially generate such longer precursors (14), whose presentation requires Nterminal processing. Several cytosolic peptidases, including tripeptidyl peptidase II (TPPII) (15), bleomycin hydrolase and puromycin-sensitive aminopeptidase (16), and the IFN-␥-inducible enzyme leucine aminopeptidase (17), may play a role in trimming some precursors to antige...

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Section: Discussionmentioning

confidence: 99%

The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism

Chang

Momburg

Bhutani

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

300

336

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“…The unique localization of the enzymes may suggest the biological functions of the oxytocinase subfamily to be strictly regulated. Indeed, it is getting evident that the enzymes belonging to this subfamily play important roles in the maintenance of homeostasis such as blood pressure regulation, angiogenesis, and maintenance of memory (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

“…Considering that A-LAP, which cleaves angiotensin II and III and kallidin, regulates blood pressure (24,46), it is tempting to speculate that L-RAP also plays a role in the regulation of blood pressure by inactivating angiotensin III and generating bradykinin. Putative ER retention machinery may play a role in the biological function of substrate peptides by regulating the secretion of the enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we and others reported that A-LAP/ERAP1 is a final processing enzyme of the precursors of major histocompatibility complex (MHC) class I-presented antigenic peptides (9,16). This enzyme was also shown to play roles in blood pressure regulation and angiogenesis (23,24). It was also reported that PSA gene-deficient mice show dwarfism and display increased anxiety and analgesia (25).…”

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confidence: 98%

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Human Leukocyte-derived Arginine Aminopeptidase

Tanioka

Hattori

Masuda

et al. 2003

Journal of Biological Chemistry

178

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In this study we report the cloning and characterization of a novel human aminopeptidase, which we designate leukocyte-derived arginine aminopeptidase (L-RAP). The sequence encodes a 960-amino acid protein with significant homology to placental leucine aminopeptidase and adipocyte-derived leucine aminopeptidase. The predicted L-RAP contains the HEXXH(X) 18 E zinc-binding motif, which is characteristic of the M1 family of zinc metallopeptidases. Phylogenetic analysis indicates that L-RAP forms a distinct subfamily with placental leucine aminopeptidase and adipocyte-derived leucine aminopeptidase in the M1 family. Immunocytochemical analysis indicates that L-RAP is located in the lumenal side of the endoplasmic reticulum. Among various synthetic substrates tested, L-RAP revealed a preference for arginine, establishing that the enzyme is a novel arginine aminopeptidase with restricted substrate specificity. In addition to natural hormones such as angiotensin III and kallidin, L-RAP cleaved various N-terminal extended precursors to major histocompatibility complex class I-presented antigenic peptides. Like other proteins involved in antigen presentation, L-RAP is induced by interferon-␥. These results indicate that L-RAP is a novel aminopeptidase that can trim the N-terminal extended precursors to antigenic peptides in the endoplasmic reticulum.

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“…Subsequently, by screening for polymorphisms in the human ERAP1 gene, Yamamoto et al (13) identified an association of K528R variant enzyme with essential hypertension. Indeed, K528R mutant ERAP1 had less enzymatic activity than the wild type (14); therefore, it is conceivable that although ERAP1 is usually retained in the ER, 2 the enzyme is secreted into the extracellular milieu in response to specific stimuli and in turn regulates blood pressure by processing peptide substrates in blood vessels.…”

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confidence: 99%

Secretion of Endoplasmic Reticulum Aminopeptidase 1 Is Involved in the Activation of Macrophages Induced by Lipopolysaccharide and Interferon-γ

Goto

Ogawa

Hattori

et al. 2011

Journal of Biological Chemistry

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Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme with an important role in processing antigenic peptides presented to class I major histocompatibility complex in the endoplasmic reticulum. In this study, we found that endoplasmic reticulum-retained ERAP1 was secreted from macrophages in response to activation by treatment with lipopolysaccharide (LPS) and interferon (IFN)-␥ and enhanced their phagocytic activity. Enhancement of the phagocytic activity of murine macrophage RAW264.7 cells induced by LPS/ IFN-␥ was inhibited by a potent aminopeptidase inhibitor, amastatin. The addition of recombinant wild-type but not inactive mutant ERAP1 to culture medium enhanced phagocytosis. These results suggest that enhancement of phagocytic activity is at least in part mediated by secreted ERAP1 through the generation of active peptides processed by the enzyme. Our data reveal ERAP1-mediated activation of macrophages for the first time and will provide new insights into the role of this enzyme in innate immunity.It is well known that endoplasmic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme belonging to the M1 family of aminopeptidases with roles in the regulation of blood pressure, angiogenesis, ectodomain shedding of several cytokine receptors, and processing of antigenic peptides presented to MHC class I molecules (1-4). Its cDNA was initially cloned as adipocyte-derived leucine aminopeptidase (5). Based on its multifunctional properties, adipocyte-derived leucine aminopeptidase is also designated ERAP1, ERAAP (endoplasmic reticulum aminopeptidase associated with antigen presentation), PILSAP (puromycin-insensitive leucine-specific aminopeptidase), and ARTS-1 (aminopeptidase regulator of TNFR1 shedding) (6 -9) (in this paper, ERAP1 is used hereafter). Although it is evident that ERAP1 plays important roles in several pathophysiological processes, its subcellular localization is still under debate. Although several reports have presented evidence showing its localization in the ER (6, 7) or cytoplasm (10) as a soluble protein, others have shown it on the cell surface as a type II membrane-spanning protein (9).ERAP1 is a monomeric zinc-metallopeptidase that shows a preference for leucine when measured by synthetic substrates (5). On the other hand, it shows relatively broad substrate specificity toward natural peptide hormones, such as angiotensin II, kallidin, and neurokinin A, which may reflect its role in the processing of various precursors of antigenic peptides presented to MHC class I molecules (11). On the basis of a preference for substrates of a specific length and C-terminal hydrophobic amino acid, the "molecular ruler" mechanism was proposed for the processing of antigenic peptides by the enzyme (12).Because ERAP1 inactivates angiotensin II and converts kallidin to bradykinin, it was initially speculated that it might regulate blood pressure (11). Subsequently, by screening for polymorphisms in the human ERAP1 gene, Yamamoto et al. (13) identified an association of K5...

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Identification of 33 polymorphisms in the adipocyte-derived leucine aminopeptidase (ALAP) gene and possible association with hypertension

Cited by 90 publications

References 13 publications

The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism

The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism

Human Leukocyte-derived Arginine Aminopeptidase

Secretion of Endoplasmic Reticulum Aminopeptidase 1 Is Involved in the Activation of Macrophages Induced by Lipopolysaccharide and Interferon-γ

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