A Fas-associated death domain protein/caspase-8-signaling axis promotes S-phase entry and maintains S6 kinase activity in T cells responding to IL-2.
Fas-associated death domain protein (FADD) constitutes an essential component of TNFR-induced apoptotic signaling. Paradoxically, FADD has also been shown to be crucial for lymphocyte development and activation. In this study, we report that FADD is necessary for long-term maintenance of S6 kinase (S6K) activity. S6 phosphorylation at serines 240 and 244 was only observed after long-term stimulation of wild-type cells, roughly corresponding to the time before S-phase entry, and was poorly induced in T cells expressing a dominantly interfering form of FADD (FADDdd), viral FLIP, or possessing a deficiency in caspase-8. Defects in S6K1 phosphorylation were also observed. However, defective S6K1 phosphorylation was not a consequence of a wholesale defect in mammalian target of rapamycin function, because 4E-BP1 phosphorylation following T cell activation was unaffected by FADDdd expression. Although cyclin D3 up-regulation and retinoblastoma hypophosphorylation occurred normally in FADDdd T cells, cyclin E expression and cyclin-dependent kinase 2 activation were markedly impaired in FADDdd T cells. These results demonstrate that a FADD/caspase-8-signaling axis promotes T cell cycle progression and sustained S6K activity.
Arechiga
Adrian F
AF
Department of Molecular Biology and Biochemistry, Center for Immunology, University of California, Irvine, CA 92697, USA.
Bell
Bryan D
BD
Leverrier
Sabrina
S
Weist
Brian M
BM
Porter
Melissa
M
Wu
Zhengqi
Z
Kanno
Yuka
Y
Ramos
Stephanie J
SJ
Ong
S Tiong
ST
Siegel
Richard
R
Walsh
Craig M
CM
D056769:Alstrom Syndrome; D000818:Animals; D053181:Caspase 8 / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D053200:Fas-Associated Death Domain Protein / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D019893:Ribosomal Protein S6 Kinases / Q000172:deficiency / Q000378:metabolism*; D016196:S Phase / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology
C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D007376:Interleukin-2; D019893:Ribosomal Protein S6 Kinases; D051357:Cyclin-Dependent Kinase 2; C505526:Casp8 protein, mouse; D053181:Caspase 8