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The collagen receptor uPARAP/Endo180 regulates collectins through unique structural elements in its FNII domain

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DOI

  1. A Survey of Novel Ligands of the Members of the Mannose Receptor Protein Family

    Research output: Book/ReportPh.D. thesisResearch

  2. Cellular uptake of collagens and implications for immune cell regulation in disease

    Research output: Contribution to journalReviewResearchpeer-review

  3. TAFI deficiency causes maladaptive vascular remodeling after hemophilic joint bleeding

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Collagen density regulates the activity of tumor-infiltrating T cells

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. CCL2/MCP-1 signaling drives extracellular matrix turnover by diverse macrophage subsets

    Research output: Contribution to journalJournal articleResearchpeer-review

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C-type lectins that contain collagen-like domains are known as collectins. These proteins are present both in the circulation and in extravascular compartments and are central players of the innate immune system, contributing to first-line defenses against viral, bacterial, and fungal pathogens. The collectins mannose-binding lectin (MBL) and surfactant protein D (SP-D) are regulated by tissue fibroblasts at extravascular sites via an endocytic mechanism governed by urokinase plasminogen activator receptor-associated protein (uPARAP or Endo180), which is also a collagen receptor. Here, we investigated the molecular mechanisms that drive the uPARAP-mediated cellular uptake of MBL and SP-D. We found that the uptake depends on residues within a protruding loop in the fibronectin type-II (FNII) domain of uPARAP that are also critical for collagen uptake. Importantly, however, we also identified FNII domain residues having an exclusive role in collectin uptake. We noted that these residues are absent in the related collagen receptor, the mannose receptor (MR or CD206), which consistently does not interact with collectins. We also show that the second C-type lectin like domain (CTLD2) is critical for the uptake of SP-D, but not MBL, indicating an additional level of complexity in the interactions between collectins and uPARAP. Finally, we demonstrate that the same molecular mechanisms enable uPARAP to engage MBL immobilized on the surface of pathogens, thereby expanding the potential biological implications of this interaction. Our study reveals molecular details of the receptor-mediated cellular regulation of collectins and offers critical clues for future investigations into collectin biology and pathology.

Original languageEnglish
JournalThe journal of biological chemistry
Volume295
Issue number27
Pages (from-to)9157-9170
Number of pages14
ISSN0021-9258
DOIs
Publication statusPublished - 3 Jul 2020

Bibliographical note

© 2020 Nørregaard et al.

ID: 60068710