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

• Published in: Cells (Basel, Switzerland) Vol. 9; no. 2; p. 351
• Main Authors: Feoktistova, Maria, Makarov, Roman, Brenji, Sihem, Schneider, Anne T, Hooiveld, Guido J, Luedde, Tom, Leverkus, Martin, Yazdi, Amir S, Panayotova-Dimitrova, Diana
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 03.02.2020; MDPI AG
• Subjects: a20; Animals; Apoptosis - drug effects; Baculoviral IAP Repeat-Containing 3 Protein - metabolism; cell death; HaCaT Cells; HeLa Cells; Humans; Inhibitor of Apoptosis Proteins - metabolism; keratinocytes; Keratinocytes - drug effects; Keratinocytes - metabolism; Mice; Models, Biological; NF-kappa B - metabolism; NF-kappaB-Inducing Kinase; nf-κb signaling; Protein Serine-Threonine Kinases - metabolism; Protein Stability - drug effects; ripoptosome; Signal Transduction - drug effects; Tumor Necrosis Factor alpha-Induced Protein 3 - deficiency; Tumor Necrosis Factor alpha-Induced Protein 3 - metabolism; Tumor Necrosis Factor-alpha - pharmacology; NF-κB signaling; ripoptosome; keratinocytes; cell death; A20
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells9020351

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.