The c-FLIP–NH 2 terminus (p22-FLIP) induces NF- κ B activation

a novel NH 2 -terminal fragment of c-FLIP (p22-FLIP). p22-FLIP turned out to be the key mediator of NF- κ B activation by c-FLIP proteins (isoforms: c-FLIP L , c-FLIP S , and c-FLIP R ) play an essential role in the regulation of death receptor–induced apoptosis. Here, we demonstrate that the cytoplasmic NH 2 -terminal procaspase-8 cleavage product of c-FLIP (p22-FLIP) found in nonapoptotic malignant cells, primary T and B cells, and mature dendritic cells (DCs) strongly induces nuclear factor 𝛋 B (NF- 𝛋 B) activity by interacting with the I 𝛋 B kinase (IKK) complex via the IKK 𝛄 subunit. Thus, in addition to inhibiting apoptosis by binding to the death-inducing signaling complex, our data demonstrate a novel mechanism by which c-FLIP controls NF- 𝛋 B activation and life/death decisions in lymphocytes and DCs. unaltered. p43-FLIP requires further processing.

[1]  L. Salmena,et al.  Cellular FLICE-inhibitory protein is required for T cell survival and cycling , 2005, The Journal of experimental medicine.

[2]  J. Tschopp,et al.  Cellular FLIP (Long Form) Regulates CD8+ T Cell Activation through Caspase-8-Dependent NF-κB Activation1 , 2005, The Journal of Immunology.

[3]  P. Krammer,et al.  c-FLIPR, a New Regulator of Death Receptor-induced Apoptosis* , 2005, Journal of Biological Chemistry.

[4]  Sankar Ghosh,et al.  Signaling to NF-kappaB. , 2004, Genes & development.

[5]  G. Salvesen,et al.  Activation of caspases-8 and -10 by FLIP(L). , 2004, The Biochemical journal.

[6]  J. Tschopp,et al.  N-Terminal Fragment of c-FLIP(L) Processed by Caspase 8 Specifically Interacts with TRAF2 and Induces Activation of the NF-κB Signaling Pathway , 2004, Molecular and Cellular Biology.

[7]  P. Krammer,et al.  Resistance of Short Term Activated T Cells to CD95-Mediated Apoptosis Correlates with De Novo Protein Synthesis of c-FLIPshort1 , 2004, The Journal of Immunology.

[8]  M. Peter,et al.  Interdimer processing mechanism of procaspase‐8 activation , 2003, The EMBO journal.

[9]  H. Nakano,et al.  The death domain kinase RIP has an essential role in DNA damage-induced NF-kappa B activation. , 2003, Genes & development.

[10]  D. Green,et al.  A unified model for apical caspase activation. , 2003, Molecular cell.

[11]  J. Tschopp,et al.  The Long Form of FLIP Is an Activator of Caspase-8 at the Fas Death-inducing Signaling Complex* , 2002, The Journal of Biological Chemistry.

[12]  J. Puck,et al.  Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency , 2002, Nature.

[13]  P. Krammer,et al.  FLICE-Inhibitory Proteins: Regulators of Death Receptor-Mediated Apoptosis , 2001, Molecular and Cellular Biology.

[14]  Margot Thome,et al.  Regulation of lymphocyte proliferation and death by flip , 2001, Nature Reviews Immunology.

[15]  P. Krammer,et al.  Cellular FLICE-inhibitory Protein Splice Variants Inhibit Different Steps of Caspase-8 Activation at the CD95 Death-inducing Signaling Complex* , 2001, The Journal of Biological Chemistry.

[16]  S. Fulda,et al.  Metabolic inhibitors sensitize for CD95 (APO-1/Fas)-induced apoptosis by down-regulating Fas-associated death domain-like interleukin 1-converting enzyme inhibitory protein expression. , 2000, Cancer research.

[17]  F. Martinon,et al.  The caspase-8 inhibitor FLIP promotes activation of NF-κB and Erk signaling pathways , 2000, Current Biology.

[18]  D. Goeddel,et al.  Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. , 2000, Immunity.

[19]  J. Tschopp,et al.  Caspase Activation Is Required for T Cell Proliferation , 1999, The Journal of experimental medicine.

[20]  Ingo Schmitz,et al.  The Role of c-FLIP in Modulation of CD95-induced Apoptosis* , 1999, The Journal of Biological Chemistry.

[21]  J. Beckmann,et al.  Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. , 1998, Immunity.

[22]  M. Hayden,et al.  Cell death attenuation by `Usurpin', a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex , 1998, Cell Death and Differentiation.

[23]  D. Goeddel,et al.  FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. , 1998, Science.

[24]  M. Peter,et al.  FLICE Is Predominantly Expressed as Two Functionally Active Isoforms, Caspase-8/a and Caspase-8/b* , 1997, The Journal of Biological Chemistry.

[25]  Matthias Mann,et al.  FLICE is activated by association with the CD95 death‐inducing signaling complex (DISC) , 1997, The EMBO journal.

[26]  J. Tschopp,et al.  Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors , 1997, Nature.

[27]  P. Krammer,et al.  Activation interferes with the APO-1 pathway in mature human T cells. , 1993, International immunology.

[28]  P. Möller,et al.  Monoclonal antibody-mediated tumor regression by induction of apoptosis. , 1989, Science.

[29]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[30]  L. Salmena,et al.  Requirement for caspase-8 in NF-kappaB activation by antigen receptor. , 2005, Science.

[31]  Zheng‐gang Liu,et al.  Molecular mechanism of TNF signaling and beyond , 2005, Cell Research.

[32]  P. Krammer,et al.  Activation or suppression of NFkappaB by HPK1 determines sensitivity to activation-induced cell death. , 2005, The EMBO journal.

[33]  M. Peter,et al.  The CD95(APO-1/Fas) DISC and beyond , 2003, Cell Death and Differentiation.

[34]  H. Shu,et al.  Activation of NF-kappaB by FADD, Casper, and caspase-8. , 2000, The Journal of biological chemistry.

[35]  L. Hood,et al.  Activation of the NF-kappaB pathway by caspase 8 and its homologs. , 2000, Oncogene.