Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions
| Autor: | John B. Lowe, Lan Zhou, Quanjian Yan, David Yao, Pamela Stanley, Lebing Wei, Yuanshuai Huang, Wei Xin, Stanton L. Gerson, Xiaoran Huang, Weihuan Wang |
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| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
Myeloid Hematopoiesis and Stem Cells Cellular differentiation T-Lymphocytes Immunology Notch signaling pathway Mice Transgenic Biology Ligands Biochemistry Mice Internal medicine medicine Animals Homeostasis Humans Lymphopoiesis RNA Messenger Cells Cultured Hydro-Lyases Bone Marrow Transplantation Fucose Mice Knockout Myelopoiesis Hyperplasia Integrases Receptors Notch Reverse Transcriptase Polymerase Chain Reaction Cell Differentiation Cell Biology Hematology Flow Cytometry Fucosyltransferases Cell biology Endocrinology medicine.anatomical_structure Notch proteins Cyclin-dependent kinase 8 Signal transduction Signal Transduction |
| Zdroj: | Blood. 117(21) |
| ISSN: | 1528-0020 |
| Popis: | Notch signaling is essential for lymphocyte development and is also implicated in myelopoiesis. Notch receptors are modified by O-fucosylation catalyzed by protein O-fucosyltransferase 1 (Pofut1). Fringe enzymes add N-acetylglucosamine to O-fucose and modify Notch signaling by altering the sensitivity of Notch receptors to Notch ligands. To address physiologic functions in hematopoiesis of Notch modified by O-fucose glycans, we examined mice with inducible inactivation of Pofut1 using Mx-Cre. These mice exhibited a reduction in T lymphopoiesis and in the production of marginal-zone B cells, in addition to myeloid hyperplasia. Restoration of Notch1 signaling rescued T lymphopoiesis and the marrow myeloid hyperplasia. After marrow transfer, both cell-autonomous and environmental cues were found to contribute to lymphoid developmental defects and myeloid hyperplasia in Pofut1-deleted mice. Although Pofut1 deficiency slightly decreased cell surface expression of Notch1 and Notch2, it completely abrogated the binding of Notch receptors with Delta-like Notch ligands and suppressed downstream Notch target activation, indicating that O-fucose glycans are critical for efficient Notch-ligand binding that transduce Notch signals. The combined data support a key role for the O-fucose glycans generated by Pofut1 in Notch regulation of hematopoietic homeostasis through modulation of Notch-ligand interactions. |
| Databáze: | OpenAIRE |
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