A proteomics-based survey reveals thrombospondin-4 as a ligand regulated by the mannose receptor in the injured lung
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved..
Receptor-mediated cellular uptake of specific ligands constitutes an important step in the dynamic regulation of individual protein levels in extracellular fluids. With a focus on the inflammatory lung, we here performed a proteomics-based search for novel ligands regulated by the mannose receptor (MR), a macrophage-expressed endocytic receptor. Wildtype and MR-deficient mice were exposed to lipopolysachharide (LPS), after which the protein content in their lung epithelial lining fluid (ELF) was compared by tandem mass tag-based mass spectrometry. More than 1200 proteins were identified in the ELF using this unbiased approach, but only six showed a statistically different abundance. Among these, an unexpected potential new ligand, thrombospondin-4 (TSP-4), displayed a striking 17-fold increased abundance in the MR-deficient mice. Experiments using exogenous addition of TSP-4 to MR-transfected CHO cells or MR-positive alveolar macrophages confirmed that TSP-4 is a ligand for MR-dependent endocytosis. Similar studies revealed that the molecular interaction with TSP-4 depends on both the lectin activity and the fibronectin type-II domain of MR and that a closely related member of the thrombospondin family, TSP-5, is also efficiently internalized by the receptor. This was unlike the other members of this protein family, including TSPs -1 and -2, which are ligands for a close MR homologue known as uPARAP. Our study shows that MR takes part in the regulation of TSP-4, an important inflammatory component in the injured lung, and that two closely related endocytic receptors, expressed on different cell types, undertake the selective endocytosis of distinct members of the thrombospondin family.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
The Journal of biological chemistry - (2024) vom: 11. Apr., Seite 107284 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nørregaard, Kirstine S [VerfasserIn] |
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| Links: |
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| Themen: |
Endocytosis |
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| Anmerkungen: |
Date Revised 13.04.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1016/j.jbc.2024.107284 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM371035163 |
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| 100 | 1 | |a Nørregaard, Kirstine S |e verfasserin |4 aut | |
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| 520 | |a Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Receptor-mediated cellular uptake of specific ligands constitutes an important step in the dynamic regulation of individual protein levels in extracellular fluids. With a focus on the inflammatory lung, we here performed a proteomics-based search for novel ligands regulated by the mannose receptor (MR), a macrophage-expressed endocytic receptor. Wildtype and MR-deficient mice were exposed to lipopolysachharide (LPS), after which the protein content in their lung epithelial lining fluid (ELF) was compared by tandem mass tag-based mass spectrometry. More than 1200 proteins were identified in the ELF using this unbiased approach, but only six showed a statistically different abundance. Among these, an unexpected potential new ligand, thrombospondin-4 (TSP-4), displayed a striking 17-fold increased abundance in the MR-deficient mice. Experiments using exogenous addition of TSP-4 to MR-transfected CHO cells or MR-positive alveolar macrophages confirmed that TSP-4 is a ligand for MR-dependent endocytosis. Similar studies revealed that the molecular interaction with TSP-4 depends on both the lectin activity and the fibronectin type-II domain of MR and that a closely related member of the thrombospondin family, TSP-5, is also efficiently internalized by the receptor. This was unlike the other members of this protein family, including TSPs -1 and -2, which are ligands for a close MR homologue known as uPARAP. Our study shows that MR takes part in the regulation of TSP-4, an important inflammatory component in the injured lung, and that two closely related endocytic receptors, expressed on different cell types, undertake the selective endocytosis of distinct members of the thrombospondin family | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a macrophage | |
| 650 | 4 | |a mass spectrometry (MS) | |
| 650 | 4 | |a protein turnover | |
| 650 | 4 | |a proteomics | |
| 650 | 4 | |a urokinase plasminogen activator-associated protein (uPARAP/Endo180) | |
| 700 | 1 | |a Jürgensen, Henrik J |e verfasserin |4 aut | |
| 700 | 1 | |a Heltberg, Signe S |e verfasserin |4 aut | |
| 700 | 1 | |a Gårdsvoll, Henrik |e verfasserin |4 aut | |
| 700 | 1 | |a Bugge, Thomas H |e verfasserin |4 aut | |
| 700 | 1 | |a Schoof, Erwin M |e verfasserin |4 aut | |
| 700 | 1 | |a Engelholm, Lars H |e verfasserin |4 aut | |
| 700 | 1 | |a Behrendt, Niels |e verfasserin |4 aut | |
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