Molecular Cloning of Adipocyte-Derived Leucine Aminopeptidase Highly Related to Placental Leucine Aminopeptidase/Oxytocinase

Hattori, Akira; Matsumoto, Hideko; Mizutani, Shigehiko; Tsujimoto, Masafumi

doi:10.1093/oxfordjournals.jbchem.a022371

Cited by 117 publications

(108 citation statements)

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“…When probing with single-amino-bond fluorogenic substrates, ERAP1 prefers hydrophobic amino acids (leucine, methionine), whereas ERAP2 displays selectivity for positively charged amino acids (arginine, lysine) (5,(9)(10)(11). However, the activity of both enzymes toward more physiological, longer substrates appears to be less restrictive (5, 9-11) and depends on additional factors such as the C terminus (12) and the internal sequence of peptides (13,14).…”

Section: P Rocessing Of Ags For Presentation By Mhc Proteins Involvesmentioning

confidence: 99%

ERAP1–ERAP2 Dimerization Increases Peptide-Trimming Efficiency

Evnouchidou

Weimershaus

Saveanu

et al. 2014

The Journal of Immunology

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The endoplasmic reticulum aminopeptidases (ERAP)1 and ERAP2 play a critical role in the production of final epitopes presented by MHC class I molecules. Formation of heterodimers by ERAP1 and ERAP2 has been proposed to facilitate trimming of epitope precursor peptides, but the effects of dimerization on ERAP function remain unknown. In this study, we produced stabilized ERAP1–ERAP2 heterodimers and found that they produced several mature epitopes more efficiently than a mix of the two enzymes unable to dimerize. Physical interaction with ERAP2 changes basic enzymatic parameters of ERAP1 and improves its substrate-binding affinity. Thus, by bringing the two enzymes in proximity and by producing allosteric effects on ERAP1, dimerization of ERAP1/2 creates complexes with superior peptide-trimming efficacy. Such complexes are likely to enhance Ag presentation by cells displaying coordinated expression of the two enzymes.

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Section: P Rocessing Of Ags For Presentation By Mhc Proteins Involvesmentioning

confidence: 99%

ERAP1–ERAP2 Dimerization Increases Peptide-Trimming Efficiency

Evnouchidou

Weimershaus

Saveanu

et al. 2014

The Journal of Immunology

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“…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).…”

mentioning

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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“…It has recently been proposed that most antigenic peptides are generated as very long precursors (Ͼ15 residues) and that tripeptidyl peptidase II (TPPII) is essential for trimming these precursors for antigen presentation (16,17). However, we find that, in vivo, proteasomes generate relatively few very long peptides, and silencing of TPPII has only a small effect on overall antigen presentation (I.A.Y., N. Bhutani, S.Z., A. L. Goldberg, and K.L.R., unpublished data).Endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1; ER-AAP) is an IFN ␥-inducible ER-localized aminopeptidase expressed in many tissues, although at widely different levels (18)(19)(20). ERAP1 was previously shown to influence the presentation of several peptides in cultured cells.…”

mentioning

confidence: 99%

“…Endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1; ER-AAP) is an IFN ␥-inducible ER-localized aminopeptidase expressed in many tissues, although at widely different levels (18)(19)(20). ERAP1 was previously shown to influence the presentation of several peptides in cultured cells.…”

mentioning

confidence: 99%

Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptidesin vivoand plays an important role in immunodominance

York

Brehm

Zendzian

et al. 2006

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

175

165

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CD8 ؉ T cells respond to short peptides bound to MHC class I molecules. Although most antigenic proteins contain many sequences that could bind to MHC class I, few of these peptides actually stimulate CD8 ؉ T cell responses. Moreover, the T cell responses that are generated often follow a very reproducible hierarchy to different peptides for reasons that are poorly understood. We find that the loss of a single enzyme, endoplasmic reticulum aminopeptidase 1 (ERAP1), in the antigen-processing pathway results in a marked shift in the hierarchy of immunodominance in viral infections, even when the responding T cells have the same T cell receptor repertoire. In mice, ERAP1 is the major enzyme that trims precursor peptides in the endoplasmic reticulum and, in this process, can generate or destroy antigenic peptides. Consequently, when ERAP1 is lost, the immune response to some viral peptides is reduced, to others increased, and to yet others unchanged. Therefore, many epitopes must be initially generated as precursors that are normally trimmed by ERAP1 before binding to MHC class I, whereas others are normally degraded by ERAP1 to lengths that are too short to bind to MHC class I. Moreover, peptide trimming and the resulting abundance of peptide-MHC complexes are dominant factors in establishing immunodominance.antigen presentation ͉ antigen processing ͉ peptidases C ells infected with a virus or otherwise producing foreign proteins can be recognized and eliminated by CD8 ϩ T cells. CD8 ϩ T cells recognize their targets through interactions between their T cell receptor (TCR) and MHC class I on the surface of the target cell. MHC class I is composed of a light chain (␤ 2 -microglobulin), a highly polymorphic heavy chain, and a small peptide that is produced by degradation of intracellular proteins.MHC class I alleles bind to peptides with a particular set of anchor residues that fit into pockets in the MHC class I peptide-binding groove. Virus proteomes typically contain many peptides with anchor residues suitable for particular MHC class I alleles, yet immune responses are generally directed toward a very limited number of epitopes. This phenomenon, in which only a few epitopes are functionally immunogenic, is known as immunodominance and is, as yet, incompletely understood (reviewed in ref. 1). Although many explanations for immunodominance have been proposed (1-9), their relative importance is not well established.The generation of most MHC class I epitopes requires proteolysis by proteasomes in the cytosol. Proteasomes can generate either the mature epitope that is ultimately presented by MHC class I molecules or precursors that are extended by several amino acids at the amino terminus. Such N-extended peptides are further processed by aminopeptidases to generate the final presented epitope. Although a number of peptidases have been proposed to play roles in MHC class I antigen presentation, few have been shown to play a major role in antigen presentation in intact cells. In cell lysates, aminopeptidases, includin...

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Molecular Cloning of Adipocyte-Derived Leucine Aminopeptidase Highly Related to Placental Leucine Aminopeptidase/Oxytocinase

Cited by 117 publications

References 0 publications

ERAP1–ERAP2 Dimerization Increases Peptide-Trimming Efficiency

ERAP1–ERAP2 Dimerization Increases Peptide-Trimming Efficiency

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

Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptidesin vivoand plays an important role in immunodominance

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