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cFLIP regulation of lymphocyte activation and development

Key Points

  • Cellular caspase-8 (FLICE)-like inhibitory protein (cFLIP) is an enzymatically inert homologue of caspase-8 that competes with caspase-8 for recruitment to the death-inducing signalling complex (DISC).

  • Paradoxically, cFLIP can also heterodimerize with caspase-8, which results in activation of the full-length caspase-8 protein.

  • Caspase-8 activity is necessary to initiate the activation of nuclear factor-κB (NF-κB) and to promote proliferation of T cells, and possibly other cell types. Increased expression of cFLIP can augment caspase-8 activity following T-cell receptor (TCR) ligation on T cells. This results in both increased proliferation, and also, ultimately, increased cell death.

  • cFLIP can associate with adaptor proteins such as tumour-necrosis-factor-receptor-associated factor 2 (TRAF2) that link to the NF-κB pathway. Therefore, increased expression of cFLIP might augment NF-κB activity in some situations, but it has also been reported to decrease NF-κB signalling following CD95 (also known as FAS) stimulation. The explanation for these disparate results is not certain at present.

  • T cells lacking cFLIP manifest decreased proliferation and survival. This might be related to decreased production of and response to interleukin-2 (IL-2) by the cFLIP-deficient T cells.

  • cFLIP might be crucial to effector function in many other cell types; for example, myeloid dendritic cells, which express high levels of cFLIP, are resistant to FAS-mediated cell death, and produce large amounts of several cytokines and mediate upregulation of CD80 and CD86 in response to CD95 ligation.

Abstract

Cellular caspase-8 (FLICE)-like inhibitory protein (cFLIP) was originally identified as an inhibitor of death-receptor signalling through competition with caspase-8 for recruitment to FAS-associated via death domain (FADD). More recently, it has been determined that both cFLIP and caspase-8 are required for the survival and proliferation of T cells following T-cell-receptor stimulation. This paradoxical finding launched new investigations of how these molecules might connect with signalling pathways that link to cell survival and growth following antigen-receptor activation. As discussed in this Review, insight gained from these studies indicates that cFLIP and caspase-8 form a heterodimer that ultimately links T-cell-receptor signalling to activation of nuclear factor-κB through a complex that includes B-cell lymphoma 10 (BCL-10), mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1 (MALT1) and receptor-interacting protein 1 (RIP1).

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Figure 1: Regulation of CD95 and T-cell-receptor-mediated signalling by caspase-8 and cFLIP.
Figure 2: Molecular structure of viral and cFLIP.
Figure 3: cFLIP modulates activation of caspase-8 and nuclear factor-κB.

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Acknowledgements

This work was supported by funding from the National Institutes of Health, the Swiss National Science Foundation, the National Cancer Institute of Canada, and the Canadian Institutes of Health Research.

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Glossary

Death domain

A protein–protein interaction domain found in many proteins that are involved in signalling and apoptosis.

Death-effector domain

(DED). A domain that is found in certain initiator caspases (for example, mammalian caspase-8) and their adaptor protein (for example, FAS-associated via death domain (FADD)). This domain mediates protein–protein interactions.

Gln-Ala-Cys-X-Gly motif

A cysteine-containing sequence that is found at the enzymatic site of caspases.

His-Gly motif

A crucial histidine sequence at the enzymatic site that is conserved in caspases.

Death-inducing signalling complex

(DISC). This complex forms after death-receptor ligation. In the case of CD95, the DISC rapidly recruits FAS-associated via death domain (FADD) through the mutual death-effector domains of CD95 and FADD, followed by caspase-8 and/or cellular caspase-8 (FLICE)-like inhibitory protein (cFLIP) recruitment by death-effector domains.

Jurkat T cell

A human leukaemic T-cell line used to study several aspects of T-cell biology and signalling, in particular signal-transduction events initiated by the T-cell receptor.

Complementation of Rag1−/− blastocysts

A method for generating lymphocytes deficient in molecules whose absence is lethal in mice. Blastocysts from a gene-knockout mouse are fused with those from Rag1−/− mice. Because Rag1−/− cells cannot give rise to lymphocytes (as their antigen-receptor genes cannot rearrange), lymphocytes that develop from these fusions will occur only from the gene-knockout cells.

Bisindolylmaleimide

An inhibitor of protein kinase C and certain G-protein-coupled receptor kinases.

Cycloheximide

An inhibitor of protein synthesis.

Autoimmune lymphoproliferative syndrome

(ALPS). A systemic lupus erythematosus (SLE)-like condition that is seen in patients bearing mutations in CD95.

BH3-only family

Members of the B-cell lymphoma (BCL-2) family that contain only the BCL-2 homology domain 3 (BH3). BH3-only members are pro-apoptotic.

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Budd, R., Yeh, WC. & Tschopp, J. cFLIP regulation of lymphocyte activation and development. Nat Rev Immunol 6, 196–204 (2006). https://doi.org/10.1038/nri1787

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