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Long and short isoforms of c-FLIP act as control checkpoints of DED filament assembly

Oncogene volume 39, pages 1756–1772 (2020)Cite this article

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Abstract

The assembly of the death-inducing signaling complex (DISC) and death effector domain (DED) filaments at CD95/Fas initiates extrinsic apoptosis. Procaspase-8 activation at the DED filaments is controlled by short and long c-FLIP isoforms. Despite apparent progress in understanding the assembly of CD95-activated platforms and DED filaments, the detailed molecular mechanism of c-FLIP action remains elusive. Here, we further addressed the mechanisms of c-FLIP action at the DISC using biochemical assays, quantitative mass spectrometry, and structural modeling. Our data strongly indicate that c-FLIP can bind to both FADD and procaspase-8 at the DED filament. Moreover, the constructed in silico model shows that c-FLIP proteins can lead to the formation of the DISCs comprising short DED filaments as well as serve as bridging motifs for building a cooperative DISC network, in which adjacent CD95 DISCs are connected by DED filaments. This network is based on selective interactions of FADD with both c-FLIP and procaspase-8. Hence, c-FLIP proteins at the DISC control initiation, elongation, and composition of DED filaments, playing the role of control checkpoints. These findings provide new insights into DISC and DED filament regulation and open innovative possibilities for targeting the extrinsic apoptosis pathway.

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Acknowledgements

We acknowledge Volkswagen Foundation (VW 90315), Wilhelm Sander-Stiftung (2017.008.01), Center of dynamic systems (CDS), funded by the EU-program ERDF (European Regional Development Fund) and DFG (LA 2386) for supporting our work.

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Author notes

  1. These authors contributed equally: Laura K. Hillert, Nikita V. Ivanisenko

Authors and Affiliations

  1. Translational Inflammation Research, Medical Faculty, Center of Dynamic Systems, Otto von Guericke University Magdeburg, Magdeburg, 39106, Germany

    Laura K. Hillert, Johannes Espe, Corinna König & Inna N. Lavrik

  2. The Federal Research Center Institute of Cytology and Genetics, SB RAS, Novosibirsk, 630090, Russia

    Nikita V. Ivanisenko & Vladimir A. Ivanisenko

  3. Institute of Internal Experimental Medicine, Medical Faculty, Otto von Guericke University Magdeburg, Magdeburg, 39120, Germany

    Thilo Kähne

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  1. Laura K. Hillert
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Correspondence to Inna N. Lavrik.

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Hillert, L.K., Ivanisenko, N.V., Espe, J. et al. Long and short isoforms of c-FLIP act as control checkpoints of DED filament assembly. Oncogene 39, 1756–1772 (2020). https://doi.org/10.1038/s41388-019-1100-3

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