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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

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....

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Bibliographic Details
Published in:The Journal of biological chemistry 2014-01, Vol.289 (2), p.1183-1191
Main Authors: Koenig, Andreas, Buskiewicz, Iwona A., Fortner, Karen A., Russell, Jennifer Q., Asaoka, Tomoko, He, You-Wen, Hakem, Razqallah, Eriksson, John E., Budd, Ralph C.
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Language:English
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Summary: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. c-FLIPL is a regulator of caspase-8 activity in T lymphocytes. Caspase-8 activity is lost upon deletion of c-FLIPL. p43FLIP rescues caspase-8 activity through Raf1, TRAF2, and RIPK1 association, augmenting ERK and NF-κB pathways. The FLIPL cleavage product p43FLIP promotes activation of pathways involved with T cell growth. This study provides new insight into the regulation of caspase-8 activity by c-FLIP.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M113.506428