An association between RBMX, a heterogeneous nuclear ribonucleoprotein, and ARTS-1 regulates extracellular TNFR1 release

Adamik, Barbara; Islam, Aminul; Rouhani, Farshid N.; Hawari, Feras; Zhang, Jing; Levine, Stewart J.

doi:10.1016/j.bbrc.2008.04.103

Cited by 29 publications

(18 citation statements)

References 10 publications

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“…It is also possible that an ER protein that competes with the proteins binding to the exon 10 sequence of ERAP1 may disrupt the interaction in the ER to induce the secretion. Although several proteins have been identified as ERAP1-binding proteins, none of these is localized in the ER (11)(12)(13)(39)(40)(41). In our preliminary results, several proteins were observed to bind to the exon 10 sequence, few of which may act as competitors of the enzyme.…”

Section: Discussionmentioning

confidence: 59%

TLR-Mediated Secretion of Endoplasmic Reticulum Aminopeptidase 1 from Macrophages

Goto

Ogawa

Nakamura

et al. 2014

The Journal of Immunology

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Macrophages play an important role in host defense under several immunological, inflammatory, and/or infectious conditions. In our previous work, we demonstrated that endoplasmic reticulum aminopeptidase 1 (ERAP1) was secreted from macrophages in response to LPS and IFN-γ, and it enhanced their phagocytic activity. In this study, we analyzed the mechanism of LPS/IFN-γ–induced ERAP1 secretion. LPS/IFN-γ–induced secretion of the enzyme from the murine macrophage cell line RAW264.7 was suppressed by polymyxin B. Several agonists of TLRs, such as Pam3CSK4, FSL-1, and ODN1826, induced its secretion. In contrast, neutralizing Abs to IFN-β and TNF-α receptor type 1 suppressed its secretion. Using murine peritoneal macrophages derived from TNF-α and type 1 IFNR knockout mice, we confirmed the involvement of these two cytokines in ERAP1 secretion. In addition, secretion of ERAP1 from both RAW264.7 cells and murine peritoneal macrophages was induced by A23187 and thapsigargin and inhibited by BAPTA-AM and the calmodulin inhibitor W7. These results suggest that LPS/IFN-γ–induced secretion of ERAP1 is mediated by TLRs via induction of intermediate cytokines such as IFN-β and TNF-α, which in turn lead to enhanced cytosolic Ca2+ levels and calmodulin activation.

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Section: Discussionmentioning

confidence: 59%

TLR-Mediated Secretion of Endoplasmic Reticulum Aminopeptidase 1 from Macrophages

Goto

Ogawa

Nakamura

et al. 2014

The Journal of Immunology

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“…Because overexpression of ERAP1 in COS-7 cells caused secretion of the enzyme, it is tempting to speculate that some ERAP1-binding proteins may act as ER retention machinery for the enzyme, and saturation or disruption of this putative machinery may cause secretion (1, 4). Several reports have described the binding proteins of the enzyme, which are localized either in the plasma membrane or cytoplasm (9,(22)(23)(24)(25). In our preliminary data, we identified a region required for ER retention of the ERAP1 molecule by constructing chimeric proteins.…”

Section: Discussionmentioning

confidence: 78%

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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“…Stewart Levine and colleagues (NIH) have reported in a series of papers that the identical gene product that they have termed ARTS-1 functions indirectly to accomplish the ectopeptidase-mediated cleavage of several cytokine receptors, including TNFR1 77 , IL-6Ra (CD126) 78 , and IL-1R2 79 . Although Dr. Shastri's data indicate that ERAAP is expressed only in the ER, the data from the Levine group's experiments in completely different cell types indicate that ARTS-1 is an integral type II membrane protein that binds TNFR1 and forms part of a multiprotein complex 80,81 . Since cytokine signaling, and particularly TNF signaling, plays a central although as yet undefined role in AS pathogenesis, an effect on cytokine receptor shedding is quite a plausible role for ERAP1 involvement with AS.…”

Section: Journal Of Rheumatologymentioning

confidence: 90%

The Role of HLA-B27 in Spondyloarthritis

Taurog¹

2010

J Rheumatol

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This article summarizes the proceedings of a one-day international workshop held in July 2009 on the role of HLA-B27 in the pathogenesis of ankylosing spondylitis (AS) and related disorders. HLA-B27 is found in about 90% of patients with AS, with an odds ratio of about 100, but the mechanism underlying this association is not known. There are currently 3 major mechanistic hypotheses for this association: (1) T cell recognition of one or more B27 presented peptides; (2) B27 heavy-chain misfolding that induces an unfolded protein response; and (3) innate immune recognition of cell-surface expressed B27 heavy-chain dimers. None of these hypotheses accounts for the tissue specificity of the inflammation characteristic of AS. These hypotheses were discussed in the context of known epidemiologic, biochemical, structural, and immunologic differences among HLA-B27 subtypes; data from the HLA-B27 transgenic rat model of spondyloarthritis; the growing list of other genes that have been found to be associated with AS; and other data on the pathogenesis of spondyloarthritis. Proposed directions for future research include expanded efforts to define similarities and differences among the B27 subtypes; further development of animal models; identifying the interactions of B27 with the products of other genes associated with AS; and continued investigation into the pathogenesis of spondyloarthritis.

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An association between RBMX, a heterogeneous nuclear ribonucleoprotein, and ARTS-1 regulates extracellular TNFR1 release

Cited by 29 publications

References 10 publications

TLR-Mediated Secretion of Endoplasmic Reticulum Aminopeptidase 1 from Macrophages

TLR-Mediated Secretion of Endoplasmic Reticulum Aminopeptidase 1 from Macrophages

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

The Role of HLA-B27 in Spondyloarthritis

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