The Absence of Core Fucose Up-regulates GnT-III and Wnt Target Genes: A POSSIBLE MECHANISM FOR AN ADAPTIVE RESPONSE IN TERMS OF GLYCAN FUNCTION* |
| |
Authors: | Ayako Kurimoto Shinobu Kitazume Yasuhiko Kizuka Kazuki Nakajima Ritsuko Oka Reiko Fujinawa Hiroaki Korekane Yoshiki Yamaguchi Yoshinao Wada Naoyuki Taniguchi |
| |
Affiliation: | From the ‡Disease Glycomic Team and ;§Structural Glycobiology Team, RIKEN Global Research Cluster, RIKEN-Max Planck Joint Research Center, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198 and ;the ¶Research Institute, Osaka Medical Center for Maternal and Child Health, Izumi, Osaka, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan |
| |
Abstract: | Glycans play key roles in a variety of protein functions under normal and pathological conditions, but several glycosyltransferase-deficient mice exhibit no or only mild phenotypes due to redundancy or compensation of glycan functions. However, we have only a limited understanding of the underlying mechanism for these observations. Our previous studies indicated that 70% of Fut8-deficient (Fut8−/−) mice that lack core fucose structure die within 3 days after birth, but the remainder survive for up to several weeks although they show growth retardation as well as emphysema. In this study, we show that, in mouse embryonic fibroblasts (MEFs) from Fut8−/− mice, another N-glycan branching structure, bisecting GlcNAc, is specifically up-regulated by enhanced gene expression of the responsible enzyme N-acetylglucosaminyltransferase III (GnT-III). As candidate target glycoproteins for bisecting GlcNAc modification, we confirmed that level of bisecting GlcNAc on β1-integrin and N-cadherin was increased in Fut8−/− MEFs. Moreover using mass spectrometry, glycan analysis of IgG1 in Fut8−/− mouse serum demonstrated that bisecting GlcNAc contents were also increased by Fut8 deficiency in vivo. As an underlying mechanism, we found that in Fut8−/− MEFs Wnt/β-catenin signaling is up-regulated, and an inhibitor against Wnt signaling was found to abrogate GnT-III expression, indicating that Wnt/β-catenin is involved in GnT-III up-regulation. Furthermore, various oxidative stress-related genes were also increased in Fut8−/− MEFs. These data suggest that Fut8−/− mice adapted to oxidative stress, both ex vivo and in vivo, by inducing various genes including GnT-III, which may compensate for the loss of core fucose functions. |
| |
Keywords: | Beta-Catenin Glycosyltransferases Lectin Mass Spectrometry (MS) Oxidative Stress Wnt Pathway Fut8 GnT-III Bisecting GlcNAc Core Fucose |
|
|