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Internal Disulfide Bonding and Glycosylation of Interleukin-7 Protect Against Proteolytic Inactivation by Neutrophil Metalloproteinases and Serine Proteases

Interleukin 7 (IL-7) is a cell growth factor with a central role in normal T cell development, survival and differentiation. The lack of IL-7–IL-7 receptor(R)-mediated signaling compromises lymphoid development, whereas increased signaling activity contributes to the development of chronic inflammat...

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Autores principales: Vandooren, Jennifer, Pereira, Rafaela Vaz Sousa, Ugarte-Berzal, Estefania, Rybakin, Vasily, Noppen, Sam, Stas, Melissa R., Bernaerts, Eline, Ganseman, Eva, Metzemaekers, Mieke, Schols, Dominique, Proost, Paul, Opdenakker, Ghislain
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278288/
https://www.ncbi.nlm.nih.gov/pubmed/34276694
http://dx.doi.org/10.3389/fimmu.2021.701739
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author Vandooren, Jennifer
Pereira, Rafaela Vaz Sousa
Ugarte-Berzal, Estefania
Rybakin, Vasily
Noppen, Sam
Stas, Melissa R.
Bernaerts, Eline
Ganseman, Eva
Metzemaekers, Mieke
Schols, Dominique
Proost, Paul
Opdenakker, Ghislain
author_facet Vandooren, Jennifer
Pereira, Rafaela Vaz Sousa
Ugarte-Berzal, Estefania
Rybakin, Vasily
Noppen, Sam
Stas, Melissa R.
Bernaerts, Eline
Ganseman, Eva
Metzemaekers, Mieke
Schols, Dominique
Proost, Paul
Opdenakker, Ghislain
author_sort Vandooren, Jennifer
collection PubMed
description Interleukin 7 (IL-7) is a cell growth factor with a central role in normal T cell development, survival and differentiation. The lack of IL-7–IL-7 receptor(R)-mediated signaling compromises lymphoid development, whereas increased signaling activity contributes to the development of chronic inflammation, cancer and autoimmunity. Gain-of-function alterations of the IL-7R and the signaling through Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) are enriched in T cell acute lymphoblastic leukemia (T-ALL) and autocrine production of IL-7 by T-ALL cells is involved in the phenotypes of leukemic initiation and oncogenic spreading. Several IL-7-associated pathologies are also characterized by increased presence of matrix metalloproteinase-9 (MMP-9), due to neutrophil degranulation and its regulated production by other cell types. Since proteases secreted by neutrophils are known to modulate the activity of many cytokines, we investigated the interactions between IL-7, MMP-9 and several other neutrophil-derived proteases. We demonstrated that MMP-9 efficiently cleaved human IL-7 in the exposed loop between the α-helices C and D and that this process is delayed by IL-7 N-linked glycosylation. Functionally, the proteolytic cleavage of IL-7 did not influence IL-7Rα binding and internalization nor the direct pro-proliferative effects of IL-7 on a T-ALL cell line (HPB-ALL) or in primary CD8(+) human peripheral blood mononuclear cells. A comparable effect was observed for the neutrophil serine proteases neutrophil elastase, proteinase 3 and combinations of neutrophil proteases. Hence, glycosylation and disulfide bonding as two posttranslational modifications influence IL-7 bioavailability in the human species: glycosylation protects against proteolysis, whereas internal cysteine bridging under physiological redox state keeps the IL-7 conformations as active proteoforms. Finally, we showed that mouse IL-7 does not contain the protease-sensitive loop and, consequently, was not cleaved by MMP-9. With the latter finding we discovered differences in IL-7 biology between the human and mouse species.
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spelling pubmed-82782882021-07-15 Internal Disulfide Bonding and Glycosylation of Interleukin-7 Protect Against Proteolytic Inactivation by Neutrophil Metalloproteinases and Serine Proteases Vandooren, Jennifer Pereira, Rafaela Vaz Sousa Ugarte-Berzal, Estefania Rybakin, Vasily Noppen, Sam Stas, Melissa R. Bernaerts, Eline Ganseman, Eva Metzemaekers, Mieke Schols, Dominique Proost, Paul Opdenakker, Ghislain Front Immunol Immunology Interleukin 7 (IL-7) is a cell growth factor with a central role in normal T cell development, survival and differentiation. The lack of IL-7–IL-7 receptor(R)-mediated signaling compromises lymphoid development, whereas increased signaling activity contributes to the development of chronic inflammation, cancer and autoimmunity. Gain-of-function alterations of the IL-7R and the signaling through Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) are enriched in T cell acute lymphoblastic leukemia (T-ALL) and autocrine production of IL-7 by T-ALL cells is involved in the phenotypes of leukemic initiation and oncogenic spreading. Several IL-7-associated pathologies are also characterized by increased presence of matrix metalloproteinase-9 (MMP-9), due to neutrophil degranulation and its regulated production by other cell types. Since proteases secreted by neutrophils are known to modulate the activity of many cytokines, we investigated the interactions between IL-7, MMP-9 and several other neutrophil-derived proteases. We demonstrated that MMP-9 efficiently cleaved human IL-7 in the exposed loop between the α-helices C and D and that this process is delayed by IL-7 N-linked glycosylation. Functionally, the proteolytic cleavage of IL-7 did not influence IL-7Rα binding and internalization nor the direct pro-proliferative effects of IL-7 on a T-ALL cell line (HPB-ALL) or in primary CD8(+) human peripheral blood mononuclear cells. A comparable effect was observed for the neutrophil serine proteases neutrophil elastase, proteinase 3 and combinations of neutrophil proteases. Hence, glycosylation and disulfide bonding as two posttranslational modifications influence IL-7 bioavailability in the human species: glycosylation protects against proteolysis, whereas internal cysteine bridging under physiological redox state keeps the IL-7 conformations as active proteoforms. Finally, we showed that mouse IL-7 does not contain the protease-sensitive loop and, consequently, was not cleaved by MMP-9. With the latter finding we discovered differences in IL-7 biology between the human and mouse species. Frontiers Media S.A. 2021-06-30 /pmc/articles/PMC8278288/ /pubmed/34276694 http://dx.doi.org/10.3389/fimmu.2021.701739 Text en Copyright © 2021 Vandooren, Pereira, Ugarte-Berzal, Rybakin, Noppen, Stas, Bernaerts, Ganseman, Metzemaekers, Schols, Proost and Opdenakker https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Vandooren, Jennifer
Pereira, Rafaela Vaz Sousa
Ugarte-Berzal, Estefania
Rybakin, Vasily
Noppen, Sam
Stas, Melissa R.
Bernaerts, Eline
Ganseman, Eva
Metzemaekers, Mieke
Schols, Dominique
Proost, Paul
Opdenakker, Ghislain
Internal Disulfide Bonding and Glycosylation of Interleukin-7 Protect Against Proteolytic Inactivation by Neutrophil Metalloproteinases and Serine Proteases
title Internal Disulfide Bonding and Glycosylation of Interleukin-7 Protect Against Proteolytic Inactivation by Neutrophil Metalloproteinases and Serine Proteases
title_full Internal Disulfide Bonding and Glycosylation of Interleukin-7 Protect Against Proteolytic Inactivation by Neutrophil Metalloproteinases and Serine Proteases
title_fullStr Internal Disulfide Bonding and Glycosylation of Interleukin-7 Protect Against Proteolytic Inactivation by Neutrophil Metalloproteinases and Serine Proteases
title_full_unstemmed Internal Disulfide Bonding and Glycosylation of Interleukin-7 Protect Against Proteolytic Inactivation by Neutrophil Metalloproteinases and Serine Proteases
title_short Internal Disulfide Bonding and Glycosylation of Interleukin-7 Protect Against Proteolytic Inactivation by Neutrophil Metalloproteinases and Serine Proteases
title_sort internal disulfide bonding and glycosylation of interleukin-7 protect against proteolytic inactivation by neutrophil metalloproteinases and serine proteases
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278288/
https://www.ncbi.nlm.nih.gov/pubmed/34276694
http://dx.doi.org/10.3389/fimmu.2021.701739
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