Semaphorin3A signaling controls Fas (CD95)-mediated apoptosis by promoting Fas translocation into lipid rafts.
Semaphorins and their receptors (plexins) have pleiotropic biologic functions, including regulation of immune responses. However, the role of these molecules inside the immune system and the signal transduction mechanism(s) they use are largely unknown. Here, we show that Semaphorin3A (Sema3A) triggers a proapoptotic program that sensitizes leukemic T cells to Fas (CD95)-mediated apoptosis. We found that Sema3A stimulation provoked Fas translocation into lipid raft microdomains before binding with agonistic antibody or FasL (CD95L). Disruption of lipid rafts reduced sensitivity to Fas-mediated apoptosis in the presence of Sema3A. Furthermore, we show that plexin-A1, together with Sema3A-binding neuropilin-1, was rapidly incorporated into membrane rafts after ligand stimulation, resulting in the transport of actin-linking proteins into Fas-enriched rafts. Cells expressing a dominant-negative mutant of plexin-A1 did not show Fas clustering and apoptosis on Sema3A/Fas costimulation. This work identifies a novel biologic function of semaphorins and presents an unexpected signaling mechanism linking semaphorin to the tumor necrosis factor family receptors.
Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona, Italy.
Simona
S
Moretti
Antonio
A
Procopio
Raffaella
R
Lazzarini
Maria Rita
MR
Rippo
Roberto
R
Testa
Maurizio
M
Marra
Luca
L
Tamagnone
Alfonso
A
Catalano
D017209:Apoptosis / Q000502:physiology*; D001854:Bone Marrow Cells / Q000473:pathology; D016923:Cell Death; D002460:Cell Line; D006801:Humans; D015458:Leukemia, T-Cell / Q000378:metabolism / Q000473:pathology; D021962:Membrane Microdomains / Q000502:physiology*; D018613:Microscopy, Confocal; D021381:Protein Transport; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040121:Semaphorin-3A / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism / Q000502:physiology*
D040121:Semaphorin-3A; D019014:fas Receptor