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.
Highlights
Tumor necrosis factor (TNF) is a central cytokine with pleiotropic functions involved in the regulation of homeostasis, controlling inflammatory cytokine production, cell survival, and cell death [1]
We showed that an elevated level of A20 results in TNF-induced cell death, which is mediated by ripoptosome formation
Our results suggest that canonical NF-κB activation and its target genes BIRC2/3 and TRAF1 (TRAF1), but not CFLAR, are important checkpoints in A20-dependent TNF-induced cell death in keratinocytes
Summary
Tumor necrosis factor (TNF) is a central cytokine with pleiotropic functions involved in the regulation of homeostasis, controlling inflammatory cytokine production, cell survival, and cell death [1]. The modification of the downstream signaling proteins by the ubiquitin system is an important switch point that directs the TNF signal towards either NF-κB activation and cell survival or cell death [5,6,7]. K63 ubiquitin chains from RIPK1 in TNF-receptor complex I, thereby limiting TNF-induced NF-κB activation. We characterized the role of A20 in the regulation of TNF-induced cell death signaling in keratinocytes. We showed that an elevated level of A20 results in TNF-induced cell death, which is mediated by ripoptosome formation In this setting, A20 plays a critical role in the regulation of both canonical and noncanonical NF-κB signaling. Our results suggest that canonical NF-κB activation and its target genes BIRC2/3 (cIAP1/2) and TRAF1 (TRAF1), but not CFLAR (cFLIP), are important checkpoints in A20-dependent TNF-induced cell death in keratinocytes. Our study provides significant insight into the critical role A20 plays in cell death regulation
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