The genetics, structure and function of the M1 aminopeptidase oxytocinase subfamily and their therapeutic potential in immune-mediated disease

Hanson, Aimee L.; Morton, Craig J.; Parker, Michael W.; Bessette, Darrell C.; Kenna, Tony J.

doi:10.1016/j.humimm.2018.11.002

Cited by 18 publications

(22 citation statements)

References 113 publications

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“…38) Overall, we postulated that ERAP1 is primarily secreted into the extracellular milieu; however, can be retained in the ER-lumen in the presence of putative binding proteins. 6,11) Further, we depleted the exon 10 coding sequence, and observed that the mutant enzyme was no longer retained in the ER-lumen and was constitutively secreted into the culture medium; thereby, supporting our hypothesis. 13) It is plausible that saturation with putative binding protein resulted in free residual ERAP1 in the ER-lumen, which was then secreted into the extracellular milieu.…”

Section: Secretion Of Erap1supporting

confidence: 77%

“…4) It is now well recognized that ERAP1 is primarily an antigenic peptide-processing enzyme located in the lumen of endoplasmic reticulum (ER-lumen), and involved in several autoimmune and inflammatory diseases. [5][6][7][8] However, there are additional activities of ERAP1 that have not been well documented to date. Here, we summarize multiple functions of ERAP1 enzyme outside ER-lumen.…”

Section: Introductionmentioning

confidence: 99%

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Endoplasmic Reticulum Aminopeptidase 1 beyond Antigenic Peptide-Processing Enzyme in the Endoplasmic Reticulum

Tsujimoto

Aoki

Ohnishi

et al. 2020

Biological & Pharmaceutical Bulletin

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Endoplasmic reticulum aminopeptidase 1 (ERAP1) is well known as a processing enzyme of antigenic peptides, which are presented to major histocompatibility complex (MHC) class I molecules in the lumen of endoplasmic reticulum. Besides antigen processing, ERAP1 performs multiple functions in various cells depending on its intracellular and extracellular localization. Of note is the secretion of ERAP1 into the extracellular milieu in response to inflammatory stimuli, which further activates immune cells including macrophages and natural killer cells. Furthermore, secreted ERAP1 enhances the expression of pro-inflammatory cytokines like tumor necrosis factor-α, interleukin-1β, and interleukin-6. Such findings indicate that ERAP1 plays a significant role in the field of innate and acquired immunity. This review summarizes the functional analyses of ERAP1 that support our current understanding of its role as more than an antigenic peptideprocessing enzyme, specifically emphasizing on its secretory form.

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Section: Secretion Of Erap1supporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum Aminopeptidase 1 beyond Antigenic Peptide-Processing Enzyme in the Endoplasmic Reticulum

Tsujimoto

Aoki

Ohnishi

et al. 2020

Biological & Pharmaceutical Bulletin

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“…Given that ERAP1 and ERAP2 have similar contribution to the field and a high sequence homology (22) that allows them to function both as homodimers and heterodimers (2, 23), we decided to clarify the following questions regarding ERAP2: (1) can ERAP2 be secreted by immune-competent activated cells? (2) If this is the case, does secreted ERAP2 retain its anti-HIV-1 properties?…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum Associated Aminopeptidase 2 (ERAP2) Is Released in the Secretome of Activated MDMs and Reduces in vitro HIV-1 Infection

et al. 2019

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Background: Haplotype-specific alternative splicing of the endoplasmic reticulum (ER) aminopeptidase type 2 (ERAP2) gene results in either full-length (FL, haplotype A) or alternatively spliced (AS, haplotype B) mRNA. HapA/HapA homozygous (HomoA) subjects show a reduced susceptibility to HIV-1 infection, probably secondary to the modulation of the antigen processing/presenting machinery. ERAP1 was recently shown to be secreted from the plasma membrane in response to activation; we investigated whether ERAP2 can be released as well and if the secreted form of this enzyme retains its antiviral function. Methods: Human monocyte derived macrophages (MDMs) were differentiated from peripheral blood mononuclear cells (PBMCs) isolated from 6 HomoA healthy controls and stimulated with IFNγ and LPS. ERAP2-FL secretion was evaluated by mass spectrometry. PBMCs (14 HomoA and 16 HomoB) and CD8-depleted PBMCs (CD8 − PBMCs) (4 HomoA and 4 HomoB) were in vitro HIV-infected in the absence/presence of recombinant human ERAP2-FL (rhERAP2) protein; p24 viral antigen quantification was used to assess viral replication. IFNγ and CD69 mRNA expression, as well as the percentage of perforin-producing CD8+ T Lymphocytes, were analyzed 3 and 7-days post in vitro HIV-1-infection, respectively. The effect of rhERAP2 addition in cell cultures on T cell apoptosis, proliferation, activation, and maturation was evaluated as well on 24 h-stimulated PBMCs. Results: ERAP2 can be secreted from human MDMs in response to IFNγ/LPS stimulation. Notably, the addition of rhERAP2 to PBMC and CD8 − PBMC cultures resulted in the reduction of viral replication, though these differences were statistically significant only in PBMCs ( p < 0.05 in both HomoA and HomoB). This protective effect was associated with an increase in IFNγ and CD69 mRNA expression and in the percentage of perforin-expressing CD107 + CD8 + cells. RhERAP2 addition also resulted in an increase in CD8 + activated lymphocyte (CD25 + HLA − DRII + ) and Effector Memory/Terminally differentiated CD8 + T cells ratio. Conclusions: This is the first report providing evidence for the release of ERAP2 in the secretome of immunocompetent cells. Data herein also indicate that exogenous ERAP2-FL exerts its protective function against HIV-1 infection, even in HomoB subjects who do not genetically produce it. Presumably, this defensive extracellular feature is only partially dependent on immune system modulation.

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“…Beside the proteasome, ~20 proteases act in the MHC-I presentation pathway and can alter presented peptides (Lázaro et al, 2015). ERAP1 is probably the most relevant example here since this aminopeptidase plays a major role in antigen processing through N-terminal peptide trimming into the endoplasmic reticulum and is associated with a number of different autoimmune diseases (Hanson et al, 2018;Serwold et al, 2002). Other aminopeptidases such as methionine aminopeptidase 2 (METAP2), leucine aminopeptidase 3 (LAP3), peptidase D (PEPD) and dipeptidyl peptidase 4 (DPP4) were showcased in this study, the latter also known to be involved in TCR-MHC signaling (Ghersi et al, 2006;Wagner et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Global Analysis of the Mammalian MHC class I Immunopeptidome at the Organism-Wide Scale

Kubiniok

Marcu

Bichmann

et al. 2020

Preprint

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Understanding the molecular principles that govern the composition of the mammalian MHC-I immunopeptidome (MHC-Ii) across different primary tissues is fundamentally important to predict how T cell respond in different contexts in vivo. Here, we performed a global analysis of the mammalian MHC-Ii from 29 and 19 primary human and mouse tissues, respectively. First, we observed that different HLA-A, -B and -C allotypes do not contribute evenly to the global composition of the MHC-Ii across multiple human tissues. Second, we found that peptides that are presented in a tissue-dependent and -independent manner share very distinct properties. Third, we discovered that proteins that were evolutionarily hyperconserved represent the primary source of the MHC-Ii at the organism-wide scale. Finally, we uncovered a remarkable antigen processing and presentation network that may drive the high level of heterogeneity of the MHC-Ii across different tissues in mammals. This study opens up new avenues toward a system-wide understanding of antigen presentation in vivo and may serve as ground work to understand tissue-dependent T cell responses in autoimmunity, infectious diseases and cancer.

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The genetics, structure and function of the M1 aminopeptidase oxytocinase subfamily and their therapeutic potential in immune-mediated disease

Cited by 18 publications

References 113 publications

Endoplasmic Reticulum Aminopeptidase 1 beyond Antigenic Peptide-Processing Enzyme in the Endoplasmic Reticulum

Endoplasmic Reticulum Aminopeptidase 1 beyond Antigenic Peptide-Processing Enzyme in the Endoplasmic Reticulum

Endoplasmic Reticulum Associated Aminopeptidase 2 (ERAP2) Is Released in the Secretome of Activated MDMs and Reduces in vitro HIV-1 Infection

Global Analysis of the Mammalian MHC class I Immunopeptidome at the Organism-Wide Scale

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