Title: 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
Authors: Charlier, E
Condé, C
Zhang, J
Deneubourg, L
Di Valentin, E
Rahmouni, S
Chariot, A
Agostinis, Patrizia
Pang, P-C
Haslam, S M
Dell, A
Penninger, J
Erneux, C
Piette, J
Gloire, G # ×
Issue Date: Feb-2010
Publisher: Nature Publishing Group
Series Title: Leukemia vol:24 issue:4 pages:821-32
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.Leukemia advance online publication, 11 February 2010; doi:10.1038/leu.2010.9.
ISSN: 0887-6924
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Cell Death Research & Therapy
× corresponding author
# (joint) last author

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