期刊
ELIFE
卷 3, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.03422
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资金
- Austrian Science Fund [P25508]
- European Research Council [250241, 2012-ADG_20120314]
- LOEWE Zentrum AdRIA Ub-Net
- Deutsche Forschungsgemeinschaft [SFB670, SFB829]
- European Commission [223404, 223151]
- Deutsche Krebshilfe [110302]
- Else Kroner-Fresenius-Stiftung
- Helmholtz Association Helmholtz Alliance Preclinical Comprehensive Cancer Center
- Human Frontier Science Program
- Deutsche Forschungsgemeinschaft
- Austrian Science Fund (FWF) [P25508] Funding Source: Austrian Science Fund (FWF)
- European Research Council (ERC) [250241] Funding Source: European Research Council (ERC)
Linear Ubiquitin chain Assembly Complex (LUBAC) is an E3 ligase complex that generates linear ubiquitin chains and is important for tumour necrosis factor (TNF) signaling activation. Mice lacking Sharpin, a critical subunit of LUBAC, spontaneously develop inflammatory lesions in the skin and other organs. Here we show that TNF receptor 1 (TNFR1)-associated death domain (TRADD)-dependent TNFR1 signaling in epidermal keratinocytes drives skin inflammation in Sharpin-deficient mice. Epidermis-restricted ablation of Fas-associated protein with death domain (FADD) combined with receptor-interacting protein kinase 3 (RIPK3) deficiency fully prevented skin inflammation, while single RIPK3 deficiency only delayed and partly ameliorated lesion development in Sharpin-deficient mice, showing that inflammation is primarily driven by TRADD- and FADD-dependent keratinocyte apoptosis while necroptosis plays a minor role. At the cellular level, Sharpin deficiency sensitized primary murine keratinocytes, human keratinocytes, and mouse embryonic fibroblasts to TNF-induced apoptosis. Depletion of FADD or TRADD in Sharpin-deficient HaCaT cells suppressed TNF-induced apoptosis, indicating the importance of FADD and TRADD in Sharpin-dependent anti-apoptosis signaling in keratinocytes.
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