Recognition by TNF-α of the GPI-anchor glycan induces apoptosis of U937 cells

Tumor necrosis factor-α (TNF-α) binds to TNF-α receptors (TNFR) to produce a hexameric (TNF-α) 3–(TNFR) 3 structure that stimulates apoptosis. We found by using ELISA that TNF-α binds to the glycosylphosphatidylinositol (GPI) anchor glycans of carcinoembryonic antigen, human placental alkaline phosp...

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Bibliographic Details
Published in:Archives of biochemistry and biophysics 2004-06, Vol.426 (2), p.298-305
Main Authors: Fukushima, Keiko, Ishiyama, Chikako, Yamashita, Katsuko
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis - drug effects
Apoptosis - physiology
Cell Cycle Proteins - metabolism
Dose-Response Relationship, Drug
GPI anchor
GPI-Linked Proteins
Humans
Mannosephosphates - metabolism
Mannosephosphates - pharmacology
Membrane Proteins - metabolism
Neoplasm Proteins - metabolism
Protein Binding
Signal Transduction - drug effects
Signal Transduction - physiology
TNF-α
Tumor Necrosis Factor-alpha - metabolism
Tumor Necrosis Factor-alpha - pharmacology
U937 Cells
β- N-acetylglucosaminyl phosphate diester
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Summary:Tumor necrosis factor-α (TNF-α) binds to TNF-α receptors (TNFR) to produce a hexameric (TNF-α) 3–(TNFR) 3 structure that stimulates apoptosis. We found by using ELISA that TNF-α binds to the glycosylphosphatidylinositol (GPI) anchor glycans of carcinoembryonic antigen, human placental alkaline phosphatase (hAP), and Tamm–Horsfall glycoprotein. These binding abilities were inhibited by 10 −6 M mannose-6-phosphate. Treatment of hAP with mild acid and phosphatase, which releases the N-acetylglucosamine (GlcNAc) β1 → phosphate → 6 residue from the GPI-anchor glycan of hAP, abrogated the binding of TNF-α to hAP. Thus, TNF-α binds to the GlcNAcβ1 → phosphate → 6Man residue in GPI-anchor glycans. To investigate whether the carbohydrate-binding ability of TNF-α is related to its physiological functions, human lymphoma U937 cells were used. TNF-α stimulates U937 cell apoptosis in a dose-dependent manner and the presence of mannose-6-phosphate inhibited this. TNF-α-dependent tyrosine phosphorylation of several proteins in U937 cells was also diminished by mannose-6-phosphate. Phosphatidylinositol-specific phospholipase C-pretreatment also inhibited this tyrosine phosphorylation. These data suggest that TNF-α stimulates U937 cell apoptosis by forming a high-affinity nanomeric (TNF-α) 3–(TNFR) 3–(GPI-anchored glycan) 3 complex. The GPI-anchored glycoprotein involved remains to be identified.
ISSN:0003-9861
1096-0384
DOI:10.1016/j.abb.2004.02.028