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1. A20 Promotes Ripoptosome Formation and TNF-Induced Apoptosis via cIAPs Regulation and NIK Stabilization in Keratinocytes

Author

Maria Feoktistova, Roman Makarov, Sihem Brenji, Anne T. Schneider, Guido J. Hooiveld, Tom Luedde, Martin Leverkus, Amir S. Yazdi, and Diana Panayotova-Dimitrova

Subjects
cell death, keratinocytes, a20, nf-κb signaling, ripoptosome, Cytology, QH573-671
Abstract

The ubiquitin-editing protein A20 (TNFAIP3) is a known key player in the regulation of immune responses in many organs. Genome-wide associated studies (GWASs) have linked A20 with a number of inflammatory and autoimmune disorders, including psoriasis. Here, we identified a previously unrecognized role of A20 as a pro-apoptotic factor in TNF-induced cell death in keratinocytes. This function of A20 is mediated via the NF-κB-dependent alteration of cIAP1/2 expression. The changes in cIAP1/2 protein levels promote NIK stabilization and subsequent activation of noncanonical NF-κB signaling. Upregulation of TRAF1 expression triggered by the noncanonical NF-κB signaling further enhances the NIK stabilization in an autocrine manner. Finally, stabilized NIK promotes the formation of the ripoptosome and the execution of cell death. Thus, our data demonstrate that A20 controls the execution of TNF-induced cell death on multiple levels in keratinocytes. This signaling mechanism might have important implications for the development of new therapeutic strategies for the treatment of A20-associated skin diseases.

Published
2020
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2. A20 Promotes Ripoptosome Formation and TNF-Induced Apoptosis via cIAPs Regulation and NIK Stabilization in Keratinocytes

Author

Sihem Brenji, Amir S. Yazdi, Diana Panayotova-Dimitrova, Roman Makarov, Martin Leverkus, Maria Feoktistova, Anne T. Schneider, Tom Luedde, and Guido J. E. J. Hooiveld

Subjects
keratinocytes, Programmed cell death, TRAF1, Ripoptosome, Apoptosis, Protein Serine-Threonine Kinases, Models, Biological, TNFAIP3, Article, Inhibitor of Apoptosis Proteins, Voeding, Metabolisme en Genomica, Mice, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Voeding, immune system diseases, hemic and lymphatic diseases, Animals, HaCaT Cells, Humans, Autocrine signalling, lcsh:QH301-705.5, Tumor Necrosis Factor alpha-Induced Protein 3, 030304 developmental biology, VLAG, Nutrition, 0303 health sciences, Protein Stability, Tumor Necrosis Factor-alpha, Chemistry, NF-kappa B, General Medicine, Baculoviral IAP Repeat-Containing 3 Protein, Metabolism and Genomics, 3. Good health, Cell biology, A20, cell death, lcsh:Biology (General), 030220 oncology & carcinogenesis, Metabolisme en Genomica, NF-κB signaling, Nutrition, Metabolism and Genomics, Tumor necrosis factor alpha, ripoptosome, HeLa Cells, Signal Transduction
Abstract

The ubiquitin-editing protein A20 (TNFAIP3) is a known key player in the regulation of immune responses in many organs. Genome-wide associated studies (GWASs) have linked A20 with a number of inflammatory and autoimmune disorders, including psoriasis. Here, we identified a previously unrecognized role of A20 as a pro-apoptotic factor in TNF-induced cell death in keratinocytes. This function of A20 is mediated via the NF-&kappa, B-dependent alteration of cIAP1/2 expression. The changes in cIAP1/2 protein levels promote NIK stabilization and subsequent activation of noncanonical NF-&kappa, B signaling. Upregulation of TRAF1 expression triggered by the noncanonical NF-&kappa, B signaling further enhances the NIK stabilization in an autocrine manner. Finally, stabilized NIK promotes the formation of the ripoptosome and the execution of cell death. Thus, our data demonstrate that A20 controls the execution of TNF-induced cell death on multiple levels in keratinocytes. This signaling mechanism might have important implications for the development of new therapeutic strategies for the treatment of A20-associated skin diseases.

Published
2020

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