Dysregulation of TGF-beta1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice.
The core fucosylation (alpha1,6-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 alpha1,6-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-beta1 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-beta1 receptor activation and signaling, as assessed by TGF-beta1 binding assays and Smad2 phosphorylation analysis. We also show that these TGF-beta1 receptor defects found in Fut8(-/-) cells can be rescued by reintroducing Fut8 into Fut8(-/-) cells. Furthermore, exogenous TGF-beta1 potentially rescued emphysema-like phenotype and concomitantly reduced MMP expression in Fut8(-/-) lung. We propose that the lack of core fucosylation of TGF-beta1 receptors is crucial for a developmental and progressive/destructive emphysema, suggesting that perturbation of this function could underlie certain cases of human emphysema.
Wang
Xiangchun
X
Department of Biochemistry, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
Inoue
Shinya
S
Gu
Jianguo
J
Miyoshi
Eiji
E
Noda
Katsuhisa
K
Li
Wenzhe
W
Mizuno-Horikawa
Yoko
Y
Nakano
Miyako
M
Asahi
Michio
M
Takahashi
Motoko
M
Uozumi
Naofumi
N
Ihara
Shinji
S
Lee
Seung Ho
SH
Ikeda
Yoshitaka
Y
Yamaguchi
Yukihiro
Y
Aze
Yoshiya
Y
Tomiyama
Yoshiaki
Y
Fujii
Junichi
J
Suzuki
Keiichiro
K
Kondo
Akihiro
A
Shapiro
Steven D
SD
Lopez-Otin
Carlos
C
Kuwaki
Tomoyuki
T
Okabe
Masaru
M
Honke
Koichi
K
Taniguchi
Naoyuki
N
D030201:Activin Receptors, Type I / Q000378:metabolism*; D000818:Animals; D004646:Emphysema / Q000209:etiology*; D005643:Fucose / Q000172:deficiency*; D005647:Fucosyltransferases / Q000172:deficiency / Q000235:genetics; D006031:Glycosylation; D008168:Lung / Q000254:growth & development* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism
D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D005643:Fucose; D005647:Fucosyltransferases; C020559:Glycoprotein 6-alpha-L-fucosyltransferase; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D020782:Matrix Metalloproteinases