SHIP-1 inhibits CD95 APO-1 Fas-induced apoptosis in primary T lymphocytes and T leukemic cells by promoting CD95 glycosylation independently of its phosphatase activity

• Published in: Leukemia Vol. 24; no. 4; pp. 821 - 832
• Main Authors: CHARLIER, E, CONDE, C, DELL, A, PENNINGER, J, ERNEUX, C, PIETTE, J, GLOIRE, G, ZHANG, J, DENEUBOURG, L, DI VALENTIN, E, RAHMOUNI, S, CHARIOT, A, AGOSTINIS, P, PANG, P.-C, HASLAM, S. M
• Format: Journal Article Web Resource
• Language: English
• Published: Avenel, NJ Nature Publishing Group 01.04.2010
• Subjects: Animals; Apoptosis; B-cell lymphoma; Biological and medical sciences; Blotting, Western; Care and treatment; CD95; CD95 antigen; Cells, Cultured; Chemical compounds; Death; Death Domain Receptor Signaling Adaptor Proteins - metabolism; Endoplasmic Reticulum; fas Receptor - antagonists & inhibitors; fas Receptor - metabolism; Flow Cytometry; Genetic aspects; Glycosylation; Health aspects; Hematologic and hematopoietic diseases; Homology; Human health sciences; Humans; Immune response; Immunologie & maladie infectieuse; Immunology & infectious disease; Inositol; Inositol Polyphosphate 5-Phosphatases; Inositols; Kinases; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma, T-Cell - metabolism; Lymphoma, T-Cell - pathology; Medical sciences; Mice; Mice, Knockout; Mortality; Myeloproliferation; Oligomerization; Pharmacology; Phosphatase; Phosphatases; Phosphatidylinositol 3,4,5-triphosphate; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Phosphoric Monoester Hydrolases - physiology; Phosphorylation; Physiological aspects; Post-translation; Protein Processing, Post-Translational; RNA, Small Interfering - pharmacology; Sciences de la santé humaine; SHIP-1; Ships; Signal Transduction; Signaling; Stimulation; T cells; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Belgium; Austria; Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1; CD95; Hematology; Enzyme; Leukemia; Phosphoric monoester hydrolases; Esterases; Malignant hemopathy; Glycosylation; T cells; Biological activity; Cell death; T-Lymphocyte; Primary; Fas Antigen; Hydrolases; Inhibitor; SHIP-1; Cancer; Apoptosis
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/leu.2010.9

SHIP-1 (SH2 (Src homology 2)-containing inositol 5'-phosphatase-1) functions as a negative regulator of immune responses by hydrolyzing phosphatidylinositol-3,4,5-triphosphate generated by phosphoinositide-3 (PI 3)-kinase activity. As a result, SHIP-1 deficiency in mice results in myeloproliferation and B-cell lymphoma. On the other hand, SHIP-1-deficient mice have a reduced T-cell population, but the underlying mechanisms are unknown. In this work, we hypothesized that SHIP-1 plays anti-apoptotic functions in T cells upon stimulation of the death receptor CD95/APO-1/Fas. Using primary T cells from SHIP-1(-/-) mice and T leukemic cell lines, we report that SHIP-1 is a potent inhibitor of CD95-induced death. We observed that a small fraction of the SHIP-1 pool is localized to the endoplasmic reticulum (ER), in which it promotes CD95 glycosylation. This post-translational modification requires an intact SH2 domain of SHIP-1, but is independent of its phosphatase activity. The glycosylated CD95 fails to oligomerize upon stimulation, resulting in impaired death-inducing signaling complex (DISC) formation and downstream apoptotic cascade. These results uncover an unanticipated inhibitory function for SHIP-1 and emphasize the role of glycosylation in the regulation of CD95 signaling in T cells. This work may also provide a new basis for therapeutic strategies using compounds inducing apoptosis through the CD95 pathway on SHIP-1-negative leukemic T cells.