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

Abstract

<jats:p>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.</jats:p>

uPARAP/Endo180: a multifaceted protein of mesenchymal cells

“…This interesting study thus assigned a novel role for uPARAP/ Endo180 in immunity. The demonstration of uPARAP/ endo180-mediated clearance of collectins by fibroblasts in injured tissue, has extended the number of previously observed biological functions of this endocytic receptor to immune-regulatory roles [45,46]. uPARAP/Endo180: a member of a trimolecular complex with the urokinase-plasminogen activator (uPA) and its receptor (uPAR) uPARAP/Endo180 acts, on certain cell types, as a co-receptor for the glycosyl phosphatidylinositol (GPI) anchored uPA-uPAR complex [47].…”

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

“…This domain is also responsible for uPARAP ´s recognition of TSP-1 ( 28 ). Within the Fn-II domain of MR, a short sequence loop has previously been identified, which is essential for the collagen interaction and which can be swapped with an equivalent sequence from a third MR family member, PLA2R, to yield a variant, MR-loop-PLA2R, that is inactive in collagen binding ( 31 ) ( Fig. 4 A ).…”

Early Stages of Ex Vivo Collagen Glycation Disrupt the Cellular Interaction and Its Remodelling by Mesenchymal Stem Cells—Morphological and Biochemical Evidence

“…However, such glycation effects on the molecular assemblies within collagen fibrils have been comparatively little studied. Collagen acts as a ligand for various substrates, including integrins, discoidin domain receptors DDR1 and 2 [47], the leukocyte receptor complex (LRC), mannose family receptor uPARAP/Endo18, and others [48], which explain its multiple biological functions. Nevertheless, the most specific cellular interaction of type I collagen was shown to be via α2β1 and α1β1 integrin receptors [49,50] and this signal is transduced through certain adapters like Src, focal adhesion kinase (FAK), paxillin, talin, vinculin, and others, which bind to the short cytoplasmic tails of integrins [49].…”