Abstract
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.
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Acknowledgements
This work was supported by grants from the Belgian National Fund for Scientific Research (FNRS, Brussels, Belgium), the Interuniversity Attraction Pole (IAP6/18, Brussels, Belgium), the concerted research action program (ARC04/09-323) and the ‘fond anticancéreux près l’Université de Liège’. CE was supported by grants from the IAP6/28 and the FNRS. AD and SMH are grateful for financial support from the Biotechnology and Biological Sciences Research Council (BBF0083091). We thank Dr S Ormenese from the imaging and flow cytometry GIGA-Research technological platform for FACS analysis, Dr S Ward for providing Tet-regulated Jurkat CD2:SHIP-1 cells, Dr E Ravet for providing TRIPΔU3 lentiviral vector and for technical advices and Drs I Lavrik and P Krammer for technical advices and helpful comments. EC was supported by the Télévie (FNRS, Brussels). GG, SR, AC and JP are Postdoctoral Researcher, Research Associate, Senior Research Associate and Research Director from the FNRS, respectively.
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Charlier, E., Condé, C., Zhang, J. et al. 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. Leukemia 24, 821–832 (2010). https://doi.org/10.1038/leu.2010.9
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DOI: https://doi.org/10.1038/leu.2010.9
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