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.

中文翻译：

---

胶原蛋白受体 uPARAP/Endo180 通过其 FNII 结构域中的独特结构元件调节集合素。


含有胶原蛋白样结构域的 C 型凝集素称为集合素。这些蛋白质存在于循环系统和血管外室中，是先天免疫系统的核心参与者，有助于针对病毒、细菌和真菌病原体的一线防御。集合素甘露糖结合凝集素 (MBL) 和表面活性剂蛋白 D (SP-D) 由血管外部位的组织成纤维细胞通过尿激酶纤溶酶原激活剂受体相关蛋白（uPARAP 或 Endo180）（也是一种胶原蛋白）控制的内吞机制进行调节受体。在这里，我们研究了驱动 uPARAP 介导的 MBL 和 SP-D 细胞摄取的分子机制。我们发现，摄取取决于 uPARAP 纤连蛋白 II 型 (FNII) 结构域中突出环内的残基，这对于胶原蛋白的摄取也至关重要。然而，重要的是，我们还发现 FNII 结构域残基在集合素吸收中具有独特的作用。我们注意到，相关胶原蛋白受体、甘露糖受体（MR 或 CD206）中不存在这些残基，它始终不与集合素相互作用。我们还表明，第二个 C 型凝集素样结构域 (CTLD2) 对于 SP-D 的摄取至关重要，但对 MBL 则不然，这表明集合素和 uPARAP 之间的相互作用具有额外的复杂性。最后，我们证明相同的分子机制使 uPARAP 能够与固定在病原体表面的 MBL 结合，从而扩大了这种相互作用的潜在生物学意义。我们的研究揭示了受体介导的集合素细胞调节的分子细节，并为未来的集合素生物学和病理学研究提供了关键线索。