A proteomics-based survey reveals thrombospondin-4 as a ligand regulated by the mannose receptor in the injured lung

Kirstine S. Nørregaard, Henrik J. Jürgensen, Signe S. Heltberg, Henrik Gårdsvoll, Thomas H. Bugge, Erwin M. Schoof, Lars H. Engelholm, Niels Behrendt*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.
Original languageEnglish
Article number107284
JournalJournal of Biological Chemistry
Volume300
Issue number5
Number of pages13
ISSN0021-9258
DOIs
Publication statusPublished - 2024

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