Human Leukocyte-derived Arginine Aminopeptidase

Tanioka, Toshihiro; Hattori, Akira; Masuda, Shigeru; Nomura, Yasuya; Nakayama, Hiroshi; Mizutani, Shigehiko; Tsujimoto, Masafumi

doi:10.1074/jbc.m305076200

Cited by 177 publications

(75 citation statements)

References 49 publications

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“…Further work is required to elucidate the role of ERAP1 in diseases associated with its polymorphisms, which include hypertension (13), cervical cancer (34,35), osteoporosis (36), and ankylosing spondylitis (37)(38)(39)(40)(41) with reference to macrophage function. It is also interesting to elucidate the dynamic aspects and pathophysiological function of ERAP2, another enzyme retained in the ER that trims antigenic peptides presented to MHC class I molecules (42)(43)(44).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Finally, two human L-RAP sequences differ in residue 392, which corresponds to PPII-Lys-463, that difference being Asn for one sequence (L-RAP-(Asn392)) or Lys for the other (L-RAP-(Lys-392)). There is no information regarding L-RAP-(Lys-392) specificity, but characterization of L-RAP-(Asn-392) demonstrates a preference for substrates with N-terminal Arg (48).…”

Section: Multiple Alignments and L-rap Modeling Suggest That In M1 Ammentioning

confidence: 99%

Homology Modeling and Site-directed Mutagenesis of Pyroglutamyl Peptidase II

Chávez‐Gutiérrez¹,

Matta‐Camacho²,

Osuna³

et al. 2006

Journal of Biological Chemistry

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“…Recently, Tanioka et al (36) have cloned from human leukocytes an aminopeptidase that they termed L-RAP. This zinc-metallopeptidase displays 49% amino acid identity to ERAP1 and is also localized in the ER of many cells and is induced by IFN-␥.…”

Section: Erap1 Prefers Peptides With a Large Hydrophobic C-terminal Rmentioning

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.

294

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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Human Leukocyte-derived Arginine Aminopeptidase

Cited by 177 publications

References 49 publications

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

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

Homology Modeling and Site-directed Mutagenesis of Pyroglutamyl Peptidase II

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

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