A20 is a known key regulator of NF-κB activity and inflammatory responses. A20 plays a role also in the control of cell death and cell death receptor signaling. Although A20 is widely accepted as an anti-apoptotic protein, we demonstrate that elevated expression of A20 in both human and murine keratinocytes results in sensitization to TNF-induced cell death. We prove that Ripoptosome formation in A20 overexpressing cells is a prerequisite for TNF-induced cell death execution. We demonstrate that both canonical and non-canonical NF-κB signaling pathways are regulated upon an increase of A20 expression. A20 dependent alterations of cIAPs and TRAF1 expression are involved in the multiple level control of cell death in keratinocytes with elevated A20 expression. Our data demonstrate the mechanistic contribution of A20 for proper control of the TNF-dependent cell death in keratinocytes. Therefore, this signaling mechanism might have important implications for the development of new therapeutic strategies in the treatment of A20-associated inflammatory skin diseases.

A20 contribution to NF-κB regulation, Ripoptosome formation and TNF-induced cell death in keratinocytes