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.
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.
Charlier
E
E
Grappe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-Research, Signal Transduction Unit, Faculty of Sciences, University of Liège, Liège, Belgium.
Condé
C
C
Zhang
J
J
Deneubourg
L
L
Di Valentin
E
E
Rahmouni
S
S
Chariot
A
A
Agostinis
P
P
Pang
P-C
PC
Haslam
S M
SM
Dell
A
A
Penninger
J
J
Erneux
C
C
Piette
J
J
Gloire
G
G
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum; D005434:Flow Cytometry; D006031:Glycosylation; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D016399:Lymphoma, T-Cell / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D019014:fas Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism
D053418:Death Domain Receptor Signaling Adaptor Proteins; D034741:RNA, Small Interfering; D019014:fas Receptor; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases