期刊
CELLS
卷 9, 期 2, 页码 -出版社
MDPI
DOI: 10.3390/cells9020351
关键词
cell death; keratinocytes; A20; NF-kappa B signaling; ripoptosome
类别
资金
- German Research Foundation DFG [Di 3-1, Le 6-1, Le 8-1]
- START grants fromthe medical faculty of the RWTHAachen [139/16]
- ERC Consolidator Grant PhaseControl [771083]
- German-Cancer-Aid [110043]
- DFG [SFB-TRR57/P06, LU 3-1]
- Ernst-Jung-Foundation Hamburg
- IZKF Aachen (medical faculty of the RWTH Aachen)
- European Research Council (ERC) [771083] Funding Source: European Research Council (ERC)
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.
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