Development of the LYVE‐1 gene with an acidic‐amino‐acid‐rich (AAAR) domain in evolution is associated with acquisition of lymph nodes and efficient adaptive immunity

Abstract

CRSBP-1 (mammalian LYVE-1) is a membrane glycoprotein highly expressed in lymphatic endothelial cells (LECs). It has multiple ligands, including hyaluronic acid (HA) and growth factors/cytokines (e.g., PDGF-BB and VEGF-A) containing CRS motifs (clusters of basic amino-acid residues). The ligand binding activities are mediated by Link module and acidic-amino-acid-rich (AAAR) domains, respectively. These CRSBP-1/LYVE-1 ligands have been shown to induce opening of lymphatic intercellular junctions in LEC monolayers and in lymphatic vessels in wild-type mice. We hypothesize that CRSBP-1/LYVE-1 ligands, particularly CRS-containing growth factors/cytokines, are secreted by immune and cancer cells for lymphatic entry during adaptive immune responses and lymphatic metastasis. We have looked into the origin of the Link module and AAAR domain of LYVE-1 in evolution and its association with the development of lymph nodes and efficient adaptive immunity. Lymph nodes represent the only major recent innovation of the adaptive immune systems in evolution particularly to mammals and bird. Here we demonstrate that the development of the LYVE-1 gene with the AAAR domain in evolution is associated with acquisition of lymph nodes and adaptive immunity. LYVE-1 from other species, which have no lymph nodes, lack the AAAR domain and efficient adaptive immunity. Synthetic CRSBP-1 ligands PDGF and VEGF peptides, which contain the CRS motifs of PDGF-BB and VEGF-A, respectively, specifically bind to CRSBP-1 but do not interact with either PDGFβR or VEGFR2. These peptides function as adjuvants by enhancing adaptive immunity of pseudorabies virus (PRV) vaccine in pigs. These results support the notion that LYVE-1 is involved in adaptive immunity in mammals.

Hyaluronan in the lymphatics: The key role of the hyaluronan receptor LYVE-1 in leucocyte trafficking

“…Importantly, the binding site for these c-terminal peptides on LYVE-1/CRSBP-1 was reported to be distinct from the HA binding surface, on the basis that the peptide ligands and HA failed to show mutual displacement. Specifically, the site has been proposed to lie downstream of the Link module, within a short region containing a spacing of 5 acidic residues termed the AAAR (Acidic Amino Acid Rich domain [106]), although the basis for this conclusion is not clear and experimental evidence to support the notion is currently lacking.…”

Hyaluronic Acid Interacting Molecules Mediated Crosstalk between Cancer Cells and Microenvironment from Primary Tumour to Distant Metastasis

“…Lymph nodes, as crucial components of the immune system, house a category of lymphocytes, including B cells and T cells. LYVE-1 is linked to the development of lymph nodes and emergence of an adaptive immunity [244]. The LYVE-1 expression pattern implies the transfer of HA from tissues into the lymphatic vessel, where it is internalised and degraded and provides a chemotactic substrate for CD44+ leukocytes and cancer cells [61].…”