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-kappa B-regulated Gene Expression

作者：Pandey Madhu S; Weigel Paul H^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289(3): 1756-1767.

DOI：10.1074/jbc.M113.510339

• Cell Signaling
• Extracellular Matrix
• Ligand-binding Protein
• NF-B Transcription Factor
• Scavenger Receptor
• Luciferase
• Stabilin-2

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.
The hyaluronan (HA) receptor for endocytosis (HARE; Stab2) clears 14 systemic ligands, including HA and heparin. Here, we used NF-B promoter-driven luciferase reporter assays to test HARE-mediated intracellular signaling during the uptake of eight ligands, whose binding sites in the HARE ectodomain were mapped by competition studies (Harris, E. N., and Weigel, P. H. (2008) Glycobiology 18, 638-648). Unique intermediate size Select-HA(TM), heparin, dermatan sulfate, and acetylated LDL stimulated dose-dependent HARE-mediated NF-B activation of luciferase expression, with half-maximal values of 10-25 nm. In contrast, chondroitin sulfate types A, C, D, and E did not stimulate NF-B activation. Moreover, degradation of endogenous IkB- (an NF-B inhibitor) was stimulated only by the signaling ligands. The stimulatory activities of pairwise combinations of the four signaling ligands were additive. The four nonstimulatory chondroitin sulfate types, which compete for HA binding, also effectively blocked HA-stimulated signaling. Clathrin siRNA decreased clathrin expression by approximate to 50% and completely eliminated NF-B-mediated signaling by all four ligands, indicating that activation of signaling complexes occurs after endocytosis. These results indicate that HARE not only binds and clears extracellular matrix degradation products (e.g. released normally or during infection, injury, tumorigenesis, or other stress situations) but that a subset of ligands also serves as signaling indicator ligands. HARE may be part of a systemic tissue-stress sensor feedback system that responds to abnormal tissue turnover or damage as a danger signal; the signaling indicator ligands would reflect the homeostatic status, whether normal or pathological, of tissue cells and biomatrix components.

• 出版日期2014-1-17