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Glycobiology Advance Access published online on April 27, 2006
Glycobiology, doi:10.1093/glycob/cwj121
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received January 18, 2006
Revised April 21, 2006
Accepted April 21, 2006

Article

Defective NO-dependent, deaminative cleavage of glypican-1 heparan sulfate in Niemann-Pick C1 fibroblasts

Katrin Mani 1, Fang Cheng 1, and Lars-Åke Fransson 1 *

1 Department of Experimental Medical Science, Division of Neuroscience, Glycobiology Group, Lund University, Biomedical Center C13, SE-221 84, Lund, Sweden

* To whom correspondence should be addressed.
Lars-Åke Fransson, E-mail: lars-ake.fransson{at}medkem.lu.se


  Abstract

Exit of recycling cholesterol from late endosomes is defective in Niemann-Pick C1 and C2 diseases. The traffic route of the recycling proteoglycan glypican-1 may also involve late endosomes, and could thus be affected in these diseases. During recycling through intracellular compartments, the heparan sulfate side-chains of glypican-1 are deaminatively degraded by nitric oxide derived from preformed S-nitroso groups in the core protein. We have now investigated whether this nitric oxide-dependent glypican-1 autoprocessing is active in fibroblasts from Niemann-Pick C1 disease. The results showed that glypican-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 nitric oxide release, resulting in deaminative cleavage of heparan sulfate. However, when nitric oxide-dependent glypican-1 autoprocessing is depressed and heparanase-catalyzed degradation of heparan sulfate remains active, a truncated glypican-1 with shorter heparan sulfate chains would prevail, resulting in fewer nitric oxide-sensitive sites/proteoglycan. Therefore, addition of ascorbate to cells with depressed autoprocessing resulted in nitration of tyrosines. Nitration was diminished when heparanase was inhibited with suramin or when glypican-1 expression was silenced by RNAi. Glypican-1 misprocessing in Niemann-Pick C1 cells could thus contribute to neurodegeneration mediated by reactive nitrogen species.

Keywords: Cholesterol/Glypican-1/Heparan sulfate/Niemann-Pick C/Nitric oxide.
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 J. Biol. Chem.Home page
K. Mani, F. Cheng, and L.-A. Fransson
Heparan Sulfate Degradation Products Can Associate with Oxidized Proteins and Proteasomes
J. Biol. Chem., July 27, 2007; 282(30): 21934 - 21944.
[Abstract] [Full Text] [PDF]

Home page
 GlycobiologyHome page
K. Mani, F. Cheng, and L.-A. Fransson
Constitutive and vitamin C-induced, NO-catalyzed release of heparan sulfate from recycling glypican-1 in late endosomes
Glycobiology, December 1, 2006; 16(12): 1251 - 1261.
[Abstract] [Full Text] [PDF]


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