期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 40, 页码 24210-24221出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.652545
关键词
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资金
- Japan Society for the Promotion of Science [B-25293006, C-23590448, 26670190, B-15K19488]
- Research Program for Development of Intelligent Tokushima Artificial Exosome (iTEX) from Tokushima University
- Grants-in-Aid for Scientific Research [26670190, 25293006, 15K08265, 15K19488, 15K08629, 25460709] Funding Source: KAKEN
The single amino acid mutation G26R in human apolipoprotein A-I (apoA-I) is associated with familial amyloid polyneuropathy III. ApoA-I carrying this mutation (apoA-IIowa) forms amyloid fibrils in vitro. Heparan sulfate (HS) is a glycosaminoglycan that is abundant at the cell surface and in the extracellular matrix. Although HS and its highly sulfated domains are involved in aggregation of amyloid-beta and accumulate in cerebral amyloid plaques of patients with Alzheimer disease and mouse models of this disease, the role of HS in familial amyloid polyneuropathy III has never been addressed. Here, we used cell models to investigate the possible role of HS in the cytotoxicity of apoA-IIowa amyloid. Wild-type CHO cells, but not pgsD-677 cells, an HS-deficient CHO mutant, demonstrated uptake of apoA-IIowa amyloid after incubation with the amyloid. Addition of sulfated glycosaminoglycans to culture media prevented interaction with and cytotoxicity of apoA-IIowa amyloid to CHO cells. Elimination of cell surface HS or inhibition of HS sulfation with chemical reagents interfered with interaction of apoA-IIowa amyloid with CHO cells. We also found that cellular interaction and cytotoxicity of apoA-IIowa amyloid were significantly attenuated in CHO cells that stably expressed the human extracellular endoglucosamine 6-sulfatases HSulf-1 and HSulf-2. Our results thus suggest that cell surface HS mediates cytotoxicity of apoA-IIowa amyloid and that enzymatic remodeling of HS mitigates the cytotoxicity.
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