Xiangchun Wang1, Shinya Inoué1, Jianguo Gu1, Eiji Miyoshi1, Katsuhisa Noda1, Wenzhe Li1, Yoko Mizuno-Horikawa1, Miyako Nakano1, Michio Asahi1, Motoko Takahashi1,2, Naonori Uozumi1, Shinji Ihara1, Seung Ho Lee1, Yoshitaka Ikeda1,2, Yukihiro Yamaguchi1,3, Y Aze1, Yoshiaki Tomiyama1, Junichi Fujii1,4, Keiichiro Suzuki1,3, Akihiro Kondo1, Steven D. Shapiro1, Carlos López‐Otín1,5, Tomoyuki Kuwaki1, Masaru Okabe1, Koichi Honke1,6, Naoyuki Taniguchi1
1Departments of Biochemistry, Internal Medicine and Molecular Science, and Glycotherapeutics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; Department of Cell Biology, Saga University School of Medicine, Saga 809-8501, Japan; Department of Biochemistry, Hyogo College of Medicine, Hyogo 663-8501, Japan; Fukui Safety Institute, Ono Pharmaceutical Co., Fukui 913-8538, Japan; Department of Biochemistry, Yamagata University School of Medicine, Yamagata 990-9585, Japan; Department of...
2saga University
3Osaka University
4Yamagata University
5Universidad de Oviedo#TAB#
6Kochi University.
Tóm tắt
The core fucosylation (α1,6-fucosylation) of glycoproteins is widely distributed in mammalian tissues, and is altered under pathological conditions. To investigate physiological functions of the core fucose, we generated α1,6-fucosyltransferase (
Fut8
)-null mice and found that disruption of
Fut8
induces severe growth retardation and death during postnatal development. Histopathological analysis revealed that
Fut8
-/-
mice showed emphysema-like changes in the lung, verified by a physiological compliance analysis. Biochemical studies indicated that lungs from
Fut8
-/-
mice exhibit a marked overexpression of matrix metalloproteinases (MMPs), such as MMP-12 and MMP-13, highly associated with lung-destructive phenotypes, and a down-regulation of extracellular matrix (ECM) proteins such as elastin, as well as retarded alveolar epithelia cell differentiation. These changes should be consistent with a deficiency in TGF-β1 signaling, a pleiotropic factor that controls ECM homeostasis by down-regulating MMP expression and inducing ECM protein components. In fact,
Fut8
-/-
mice have a marked dysregulation of TGF-β1 receptor activation and signaling, as assessed by TGF-β1 binding assays and Smad2 phosphorylation analysis. We also show that these TGF-β1 receptor defects found in
Fut8
-/-
cells can be rescued by reintroducing
Fut8
into
Fut8
-/-
cells. Furthermore, exogenous TGF-β1 potentially rescued emphysema-like phenotype and concomitantly reduced MMP expression in
Fut8
-/-
lung. We propose that the lack of core fucosylation of TGF-β1 receptors is crucial for a developmental and progressive/destructive emphysema, suggesting that perturbation of this function could underlie certain cases of human emphysema.
