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Fucosylation: Keep those lymphocytes rolling

Histochemical detection of fucosylated (green) glycans in cortical sections of Slc35c1+/+ (D) and Slc35c1-/- (D') mice

Copyright © 2007 ASBMB

Fucose residues predominantly occur at the terminal position of cell-surface glycans. They are distinguished from other hexoses by carrying a reduced hydroxy group at the 6^th carbon atom. Fucosylation of the Notch receptor highlights the influence that fucose can have on cell signaling. Fucose also plays a role in cell adhesion and migration — including the rolling of leukocytes along endothelial cell walls — where selectins and integrins act as receptor proteins that bind fucose- and sialic acid-containing glycans. Fucose is synthesized in the cytosol and transported as GDP-fucose into the Golgi by the transporter SLC35C1, where it is used for glycosylation. In humans, SLC35C1 deficiency causes glycoprotein hypofucosylation, which presents as the disease "Congenital disorder of glycosylation type IIc" (CDG-IIc), also known as Leukocyte Adhesion Deficiency II (LADII). Now, in The Journal of Biological Chemistry, Hellbusch et al. use a mouse model to describe the physiological and molecular details of transporter deficiency.

GDP-fucose transporter knockout mice (Slc35c1^–/–) had no visible defects at birth but exhibited retarded growth and reduced weight gain within the first few days of life. Knockout mice had a mortality of one in three within the first week. Organ structure was normal in adult Slc35c1^–/– mice with the exception of the lungs, which showed dilated alveoles and thinner alveolar walls.

Hellbusch et al. investigated lymphocyte motility — a process known to be strongly affected by hypofucosylation — in Slc35c1^–/– mice. They discovered that granulocyte fucosylation was at only 1.5% that of wildtype animals, which lead to a complete absence of selectin binding. At the same time, the percentage of rolling leukocytes and the velocity of rolling were markedly reduced in knockout mice. Direct blocking of selectin did not aggravate the already reduced lymphocyte motility. This suggests that the absence of terminal fucose alters the structure of the L-selectin glycan ligand significantly enough to inhibit selectin binding and reduce lymphocyte motility.

These results indicate that L-selectin ligand function in leukocytes is dependent upon Slc35c1 GDP-fucose transport activity and that fucose has a role in leukocyte function and growth regulation. The reduction in body growth and impairment of leukocyte function in Slc35c1^–/– mice are similar to the symptoms of LADII in humans. Except for lung morphology, fucosylation deficiency appears to impact organ function rather than organ structure. Interestingly, the observed abnormalities in lung cells are similar to defects found in mice lacking fucosyltransferase VIII. These defects have previously been attributed to alterations in transforming growth factor (TGF) signaling. Further studies are needed to determine whether Slc35c1^–/– mice also exhibit alterations in TGF signaling.

Author: Mirko von Elstermann