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

J Immunol. 2007 Oct 15;179(8):5291-300. doi: 10.4049/jimmunol.179.8.5291.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alstrom Syndrome
  • Animals
  • Caspase 8 / genetics
  • Caspase 8 / physiology*
  • Cells, Cultured
  • Cyclin-Dependent Kinase 2 / deficiency
  • Cyclin-Dependent Kinase 2 / metabolism
  • Cyclin-Dependent Kinase 2 / physiology
  • Enzyme Activation / genetics
  • Enzyme Activation / immunology
  • Fas-Associated Death Domain Protein / physiology*
  • Humans
  • Interleukin-2 / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phosphorylation
  • Ribosomal Protein S6 Kinases / deficiency
  • Ribosomal Protein S6 Kinases / metabolism*
  • S Phase / genetics
  • S Phase / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • T-Lymphocyte Subsets / cytology*
  • T-Lymphocyte Subsets / enzymology*
  • T-Lymphocyte Subsets / immunology

Substances

  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • Interleukin-2
  • Ribosomal Protein S6 Kinases
  • Cyclin-Dependent Kinase 2
  • Casp8 protein, mouse
  • Caspase 8