Alpha-Mannosidase-II Deficiency Results in Dyserythropoiesis and Unveils an Alternate Pathway in Oligosaccharide Biosynthesis

Chui, Daniel; Oh-eda, Masayoshi; Liao, Yiping; Panneerselvam, K.; Lal, Anita; Marek, Kurt W.; Freeze, Hudson H.; Moremen, Kelley W.; Fukuda, Michiko N.; Marth, Jamey D.

doi:10.1016/s0092-8674(00)80322-0

Cited by 193 publications

(151 citation statements)

References 51 publications

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“…Inactivation of ␣-mannosidase II (22,23,25), and ␣-mannosidase IIx (24,25) individually reduces overall complex N-glycan synthesis significantly, but the mice are viable, albeit with different consequences, causing anemia or male infertility, respectively. However, ablation of both genes completely abrogates complex N-glycan formation with the accumulation of hybrid structures (25,38).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the unique cell-and tissuespecific roles of individual members of multigene enzyme families have also been revealed by these studies. For example, ␣-mannosidase II-deficient mice develop dyserythropoietic anemia and autoimmune disease (22,23), yet disruption of the mouse ␣-mannosidase IIx gene results in hypospermatogenesis and male infertility (24). However, ablation of both ␣-mannosidase II and IIx completely abrogates complex N-glycan biosynthesis with the accumulation of hybrid structures, and causes hepatic and pulmonary ultrastructural defects.…”

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confidence: 99%

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Respiratory Distress and Neonatal Lethality in Mice Lacking Golgi α1,2-Mannosidase IB Involved in N-Glycan Maturation

Tremblay

Kovács

Daniels

et al. 2007

Journal of Biological Chemistry

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There are three mammalian Golgi ␣1,2-mannosidases, encoded by different genes, that form Man 5 GlcNAc 2 from Man 8-9 GlcNAc 2 for the biosynthesis of hybrid and complex N-glycans. Northern blot analysis and in situ hybridization indicate that the three paralogs display distinct developmental and tissue-specific expression. The physiological role of Golgi ␣1,2-mannosidase IB was investigated by targeted gene ablation. The null mice have normal gross appearance at birth, but they display respiratory distress and die within a few hours. Histology of fetal lungs the day before birth indicate some delay in development, whereas neonatal lungs show extensive pulmonary hemorrhage in the alveolar region. No significant histopathological changes occur in other tissues. No remarkable ultrastructural differences are detected between wild type and null lungs. The membranes of a subset of bronchiolar epithelial cells are stained with lectins from Phaseolus vulgaris (leukoagglutinin and erythroagglutinin) and Datura stramonium in wild type lungs, but this staining disappears in lungs from null mice. Mass spectrometry of N-glycans from different tissues shows no significant changes in global N-glycans of null mice. Therefore, only a few glycoproteins required for normal lung function depend on ␣1,2-mannosidase IB for maturation. There are no apparent differences in the expression of several lung epithelial cell and endothelial cell markers between null and wild type mice. The ␣1,2-mannosidase IB null phenotype differs from phenotypes caused by ablation of other enzymes in N-glycan biosynthesis and from other mouse gene disruptions that affect pulmonary development and function.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Respiratory Distress and Neonatal Lethality in Mice Lacking Golgi α1,2-Mannosidase IB Involved in N-Glycan Maturation

Tremblay

Kovács

Daniels

et al. 2007

Journal of Biological Chemistry

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“…A 1.5-kb genomic fragment upstream of exon 1, a 4.5-kb lacZ gene (excised from the p␤gal-Basic vector; BD Biosciences), a 1.7-kb PGKneo gene (excised from the pFlox vector (22)), and a 7.3-kb genomic fragment downstream of exon 6, were successively subcloned in the pMC1DT-3 vector (23), generating the Cth gene-targeting construct. The vector was linearized with NotI and transfected into 129/Sv embryonic stem cells (Dainippon Sumitomo Pharma, Osaka, Japan) by electroporation.…”

Section: Methodsmentioning

confidence: 99%

Cystathionine γ-Lyase-deficient Mice Require Dietary Cysteine to Protect against Acute Lethal Myopathy and Oxidative Injury

Ishii

Akahoshi

Yamada

et al. 2010

Journal of Biological Chemistry

202

226

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Cysteine is considered a nonessential amino acid in mammals as it is synthesized from methionine via trans-sulfuration. However, premature infants or patients with hepatic failure may require dietary cysteine due to a lack of cystathionine ␥-lyase (CTH), a key trans-sulfuration enzyme. Here, we generated CTH-deficient (Cth ؊/؊ ) mice as an animal model of cystathioninemia/cystathioninuria. Cth ؊/؊ mice developed normally in general but displayed hypercystathioninemia/hyperhomocysteinemia though not hypermethioninemia. When fed a low cyst(e)ine diet, Cth ؊/؊ mice showed acute skeletal muscle atrophy (myopathy) accompanied by enhanced gene expression of asparagine synthetase and reduced contents of glutathione in livers and skeletal muscles, and intracellular accumulation of LC3 and p62 in skeletal myofibers; they finally died of severe paralysis of the extremities. Cth ؊/؊ hepatocytes required cystine in a culture medium and showed greater sensitivity to oxidative stress. Cth ؊/؊ mice exhibited systemic vulnerability to oxidative injury, which became more prominent when they were fed the low cyst(e)ine diet. These results reveal novel roles of trans-sulfuration previously unrecognized in mice lacking another trans-sulfuration enzyme cystathionine ␤-synthase (Cbs ؊/؊ ). Because Cbs ؊/؊ mice display hyperhomocysteinemia and hypermethioninemia, our results raise questions against the homocysteine-based etiology of CBS deficiency and the current newborn screening for homocysteinemia using Guthrie's method, which detects hypermethioninemia.

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“…5a), and no further inhibition was achieved at 1 M (data not shown). Swainsonine inhibited the majority of L-PHA staining, yet a small population of L-PHA-positive cells persisted, suggesting a minor or alternate pathway to complex-type N-glycans that uses ␣-mannosidase IIX is functional in these cells (24). Naive T cells (CD4 ϩ CD45RO Ϫ ) were stimulated with anti-CD3 and anti-CD28.…”

Section: Mgat5 and Ifn-␥/il-4 Production By Cd4 ϩ Cellsmentioning

confidence: 99%

N-Acetylglucosaminyltransferase V (Mgat5)-Mediated N-Glycosylation Negatively Regulates Th1 Cytokine Production by T Cells

Morgan

Gao

Pawling

et al. 2004

The Journal of Immunology

139

134

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The differentiation of naive CD4+ T cells into either proinflammatory Th1 or proallergic Th2 cells strongly influences autoimmunity, allergy, and tumor immune surveillance. We previously demonstrated that β1,6GlcNAc-branched complex-type (N-acetylglucosaminyltransferase V (Mgat5)) N-glycans on TCR are bound to galectins, an interaction that reduces TCR signaling by opposing agonist-induced TCR clustering at the immune synapse. Mgat5−/− mice display late-onset spontaneous autoimmune disease and enhanced resistance to tumor progression and metastasis. In this study we examined the role of β1,6GlcNAc N-glycan expression in Th1/Th2 cytokine production and differentiation. β1,6GlcNAc N-glycan expression is enhanced by TCR stimulation independent of cell division and declines at the end of the stimulation cycle. Anti-CD3-activated splenocytes and naive T cells from Mgat5−/− mice produce more IFN-γ and less IL-4 compared with wild-type cells, the latter resulting in the loss of IL-4-dependent down-regulation of IL-4Rα. Swainsonine, an inhibitor of Golgi α-mannosidase II, blocked β1,6GlcNAc N-glycan expression and caused a similar increase in IFN-γ production by T cells from humans and mice, but no additional enhancement in Mgat5−/− T cells. Mgat5 deficiency did not alter IFN-γ/IL-4 production by polarized Th1 cells, but caused an ∼10-fold increase in IFN-γ production by polarized Th2 cells. These data indicate that negative regulation of TCR signaling by β1,6GlcNAc N-glycans promotes development of Th2 over Th1 responses, enhances polarization of Th2 cells, and suggests a mechanism for the increased autoimmune disease susceptibility observed in Mgat5−/− mice.

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Alpha-Mannosidase-II Deficiency Results in Dyserythropoiesis and Unveils an Alternate Pathway in Oligosaccharide Biosynthesis

Cited by 193 publications

References 51 publications

Respiratory Distress and Neonatal Lethality in Mice Lacking Golgi α1,2-Mannosidase IB Involved in N-Glycan Maturation

Respiratory Distress and Neonatal Lethality in Mice Lacking Golgi α1,2-Mannosidase IB Involved in N-Glycan Maturation

Cystathionine γ-Lyase-deficient Mice Require Dietary Cysteine to Protect against Acute Lethal Myopathy and Oxidative Injury

N-Acetylglucosaminyltransferase V (Mgat5)-Mediated N-Glycosylation Negatively Regulates Th1 Cytokine Production by T Cells

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