title: 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.
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.
authors.affiliation: Disease Glycomic Team, RIKEN-Max Planck Joint Research Center, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kurimoto
authors.affiliation: Disease Glycomic Team, RIKEN-Max Planck Joint Research Center, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Kitazume
authors.affiliation: Disease Glycomic Team, RIKEN-Max Planck Joint Research Center, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kizuka
authors.affiliation: Disease Glycomic Team, RIKEN-Max Planck Joint Research Center, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nakajima
authors.affiliation: Disease Glycomic Team, RIKEN-Max Planck Joint Research Center, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Oka
authors.affiliation: Disease Glycomic Team, RIKEN-Max Planck Joint Research Center, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198.
authors.forename: Reiko
authors.initials: R
authors.lastname: Fujinawa
authors.affiliation: Disease Glycomic Team, RIKEN-Max Planck Joint Research Center, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Korekane
authors.affiliation: Structural Glycobiology Team, RIKEN Global Research Cluster, RIKEN-Max Planck Joint Research Center, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Research Institute, Osaka Medical Center for Maternal and Child Health, Izumi, Osaka, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Wada
authors.affiliation: Disease Glycomic Team, RIKEN-Max Planck Joint Research Center, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198. Electronic address: tani52@wd5.so-net.ne.jp.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005643:Fucose / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011134:Polysaccharides / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D011134:Polysaccharides; D051153:Wnt Proteins; D005643:Fucose; D017351:N-Acetylglucosaminyltransferases; C054599:beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase
keywords: Beta-Catenin; Bisecting GlcNAc; Core Fucose; Fut8; Glycosyltransferases; GnT-III; Lectin; Mass Spectrometry (MS); Oxidative Stress; Wnt Pathway