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Open AccessArticle

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

1
Department of Dermatology and Allergology, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
2
Department of Medicine III, Department of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
3
Nutrition, Metabolism & Genomics Group, Division of Human Nutrition & Health, Wageningen University, 6700 AA Wageningen; The Netherlands
*
Author to whom correspondence should be addressed.
Deceased.
Cells 2020, 9(2), 351; https://doi.org/10.3390/cells9020351
Received: 13 January 2020 / Revised: 29 January 2020 / Accepted: 1 February 2020 / Published: 3 February 2020
(This article belongs to the Section Cell Signaling and Regulated Cell Death)
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. View Full-Text
Keywords: cell death; keratinocytes; A20; NF-κB signaling; ripoptosome cell death; keratinocytes; A20; NF-κB signaling; ripoptosome
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Feoktistova, M.; Makarov, R.; Brenji, S.; Schneider, A.T.; Hooiveld, G.J.; Luedde, T.; Leverkus, M.; Yazdi, A.S.; Panayotova-Dimitrova, D. A20 Promotes Ripoptosome Formation and TNF-Induced Apoptosis via cIAPs Regulation and NIK Stabilization in Keratinocytes. Cells 2020, 9, 351.

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