Defective nitric oxide-dependent, deaminative cleavage of glypican-1 heparan sulfate in Niemann-Pick C1 fibroblasts

Glycobiology
Katrin ManiLars-Ake Fransson

Abstract

Exit of recycling cholesterol from late endosomes is defective in Niemann-Pick C1 (NPC1) and Niemann-Pick C2 (NPC2) diseases. The traffic route of the recycling proteoglycan glypican-1 (Gpc-1) may also involve late endosomes and could thus be affected in these diseases. During recycling through intracellular compartments, the heparan sulfate (HS) side chains of Gpc-1 are deaminatively degraded by nitric oxide (NO) derived from preformed S-nitroso groups in the core protein. We have now investigated whether this NO-dependent Gpc-1 autoprocessing is active in fibroblasts from NPC1 disease. The results showed that Gpc-1 autoprocessing was defective in these cells and, furthermore, greatly depressed in normal fibroblasts treated with U18666A (3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one), a compound widely used to induce cholesterol accumulation. In both cases, autoprocessing was partially restored by treatment with ascorbate which induced NO release, resulting in deaminative cleavage of HS. However, when NO-dependent Gpc-1 autoprocessing is depressed and heparanase-catalyzed degradation of HS remains active, a truncated Gpc-1 with shorter HS chains would prevail, resulting in fewer NO-sensitive sites/proteoglycan. Therefore,...Continue Reading

References

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Citations

May 30, 2009·Glycoconjugate Journal·Gabriel Svensson, Katrin Mani
Mar 9, 2007·Trends in Molecular Medicine·Lars-Ake Fransson, Katrin Mani
Jun 11, 2009·British Journal of Pharmacology·J MandlG Bánhegyi
Jun 20, 2017·Journal of Proteome Research·Jun-Ichi FurukawaYasuro Shinohara
Nov 14, 2014·The Journal of Biological Chemistry·Liliana Schaefer
Jun 2, 2007·The Journal of Biological Chemistry·Katrin ManiLars-Ake Fransson
Jan 21, 2017·Molecular Neurodegeneration·Clinton CaveShanthini Sockanathan

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