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The c-FLIPL cleavage product p43FLIP promotes activation of extracellular signal-regulated kinase (ERK), nuclear factor κB (NF-κB), and caspase-8 and T cell survival.

Publication ,  Journal Article
Koenig, A; Buskiewicz, IA; Fortner, KA; Russell, JQ; Asaoka, T; He, Y-W; Hakem, R; Eriksson, JE; Budd, RC
Published in: J Biol Chem
January 10, 2014

Caspase-8 is now appreciated to govern both apoptosis following death receptor ligation and cell survival and growth via inhibition of the Ripoptosome. Cells must therefore carefully regulate the high level of caspase-8 activity during apoptosis versus the modest levels observed during cell growth. The caspase-8 paralogue c-FLIP is a good candidate for a molecular rheostat of caspase-8 activity. c-FLIP can inhibit death receptor-mediated apoptosis by competing with caspase-8 for recruitment to FADD. However, full-length c-FLIPL can also heterodimerize with caspase-8 independent of death receptor ligation and activate caspase-8 via an activation loop in the C terminus of c-FLIPL. This triggers cleavage of c-FLIPL at Asp-376 by caspase-8 to produce p43FLIP. The continued function of p43FLIP has, however, not been determined. We demonstrate that acute deletion of endogenous c-FLIP in murine effector T cells results in loss of caspase-8 activity and cell death. The lethality and caspase-8 activity can both be rescued by the transgenic expression of p43FLIP. Furthermore, p43FLIP associates with Raf1, TRAF2, and RIPK1, which augments ERK and NF-κB activation, IL-2 production, and T cell proliferation. Thus, not only is c-FLIP the initiator of caspase-8 activity during T cell activation, it is also an initial caspase-8 substrate, with cleaved p43FLIP serving to both stabilize caspase-8 activity and promote activation of pathways involved with T cell growth.

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

January 10, 2014

Volume

289

Issue

2

Start / End Page

1183 / 1191

Location

United States

Related Subject Headings

  • TNF Receptor-Associated Factor 2
  • T-Lymphocytes
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • Peptide Fragments
  • NF-kappa B
  • Mice, Transgenic
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
 

Citation

APA
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ICMJE
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Koenig, A., Buskiewicz, I. A., Fortner, K. A., Russell, J. Q., Asaoka, T., He, Y.-W., … Budd, R. C. (2014). The c-FLIPL cleavage product p43FLIP promotes activation of extracellular signal-regulated kinase (ERK), nuclear factor κB (NF-κB), and caspase-8 and T cell survival. J Biol Chem, 289(2), 1183–1191. https://doi.org/10.1074/jbc.M113.506428
Koenig, Andreas, Iwona A. Buskiewicz, Karen A. Fortner, Jennifer Q. Russell, Tomoko Asaoka, You-Wen He, Razqallah Hakem, John E. Eriksson, and Ralph C. Budd. “The c-FLIPL cleavage product p43FLIP promotes activation of extracellular signal-regulated kinase (ERK), nuclear factor κB (NF-κB), and caspase-8 and T cell survival.J Biol Chem 289, no. 2 (January 10, 2014): 1183–91. https://doi.org/10.1074/jbc.M113.506428.
Koenig A, Buskiewicz IA, Fortner KA, Russell JQ, Asaoka T, He Y-W, et al. The c-FLIPL cleavage product p43FLIP promotes activation of extracellular signal-regulated kinase (ERK), nuclear factor κB (NF-κB), and caspase-8 and T cell survival. J Biol Chem. 2014 Jan 10;289(2):1183–91.
Koenig, Andreas, et al. “The c-FLIPL cleavage product p43FLIP promotes activation of extracellular signal-regulated kinase (ERK), nuclear factor κB (NF-κB), and caspase-8 and T cell survival.J Biol Chem, vol. 289, no. 2, Jan. 2014, pp. 1183–91. Pubmed, doi:10.1074/jbc.M113.506428.
Koenig A, Buskiewicz IA, Fortner KA, Russell JQ, Asaoka T, He Y-W, Hakem R, Eriksson JE, Budd RC. The c-FLIPL cleavage product p43FLIP promotes activation of extracellular signal-regulated kinase (ERK), nuclear factor κB (NF-κB), and caspase-8 and T cell survival. J Biol Chem. 2014 Jan 10;289(2):1183–1191.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

January 10, 2014

Volume

289

Issue

2

Start / End Page

1183 / 1191

Location

United States

Related Subject Headings

  • TNF Receptor-Associated Factor 2
  • T-Lymphocytes
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • Peptide Fragments
  • NF-kappa B
  • Mice, Transgenic
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice