Hyaluronic Acid Receptor for Endocytosis (HARE)-mediated Endocytosis of Hyaluronan, Heparin, Dermatan Sulfate, and Acetylated Low Density Lipoprotein (AcLDL), but Not Chondroitin Sulfate Types A, C, D, or E, Activates NF-κB-regulated Gene Expression

Abstract

Background: HARE mediates systemic clearance of 14 ECM-or stress-derived ligands. Hyaluronan uptake activates NF-B. Results: Heparin, dermatan sulfate, and acetylated LDL also activated NF-B; chondroitin sulfates types A, C, D, and E did not. Conclusion: A subset of HARE ligands activates signaling and gene expression. Significance: HARE may be a systemic tissue-stress sensor that responds to abnormal ECM turnover and damage.

A Hyaluronan Receptor for Endocytosis (HARE) Link Domain N-Glycan Is Required for Extracellular Signal-regulated Kinase (ERK) and Nuclear Factor-κB (NF-κB) Signaling in Response to the Uptake of Hyaluronan but Not Heparin, Dermatan Sulfate, or Acetylated Low Density Lipoprotein (LDL)

“…Similarly, WT cells treated with either HA preparation showed significant gene activation (p Ͻ 0.001). In contrast, the N2280A cells showed no NF-B-mediated gene activation in the pres- A mixing control with the two ligands was performed to verify that HA did not interfere with Hep signaling in N2280A cells; in WT cells, signaling responses with both HA and Hep are additive (18). The activation of 5 nM Hep was not affected by the presence of 5 nM HA, consistent with the lack of competition for binding by the two ligands (Fig.…”

“…The localization of these inactive NF-B complexes with IB-␣/␤ is also shifted from the nucleus to the cytoplasm. We previously found that in the absence of the LUC recorder gene plasmids, HARE-mediated endocytosis of HA, Hep, DS, or AcLDL leads to degradation of ϳ50% of the cellular IB-␣ protein in Ͻ1 h (18). To determine whether this endogenous signaling cascade is altered by the loss of the Link domain N-glycan, we assessed degradation of IB-␣ in WT (Fig.…”

“…min and processed as described previously (18). Equal amounts of cell lysate protein were resolved on 10% SDS-PAGE, transferred to nitrocellulose, and probed with anti-IB-␣ Ab.…”

“…We reported that HA⅐HARE interactions stimulate NF-B activation of gene expression and that HARE displays an HA size-sensing mechanism for detecting and responding to a narrow size range (40 -400 kDa) of HA degradation products (17). We examined seven other HARE ligands for their ability to stimulate signaling and discovered that DS, AcLDL, or Hep uptake also activates NF-B-mediated gene expression but that CS types A, C, D, and E are inactive (18). As with HA, the latter four ligands also bind to the Link domain, and all four can compete for HA binding.…”

Hyaluronan and hyaluronidase, which is better for embryo development?

“…Through binding to its specific receptors like CD44 and HARE (Pandey and Weigel 2014), hyaluronan and its fragments are involved in signalling pathways that can influence cellular functions though regulation of gene expression. For example, HA is associated to increased growth factors expression during particular healing processes including epidermal growth factor (EGF), insulin-like growth factor (IGF) (Saliba, et al 2014).…”