Snehlata Kumari, Younes Redouane, Jaime Lopez-Mosqueda, Ryoko Shiraishi, Malgorzata Romanowska, Stefan Lutzmayer, Jan Kuiper, Conception Martinez, Ivan Đikić, Manolis Pasparakis, Fumiyo Ikeda
- 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.
MetadatenAuthor: | Snehlata Kumari, Younes Redouane, Jaime Lopez-Mosqueda, Ryoko Shiraishi, Malgorzata Romanowska, Stefan Lutzmayer, Jan Kuiper, Conception Martinez, Ivan ĐikićORCiDGND, Manolis Pasparakis, Fumiyo Ikeda |
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URN: | urn:nbn:de:hebis:30:3-377974 |
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DOI: | https://doi.org/10.7554/eLife.03422 |
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ISSN: | 2050-084X |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/25443631 |
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Parent Title (English): | eLife |
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Publisher: | eLife Sciences Publications |
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Place of publication: | Cambridge |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2014/12/02 |
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Date of first Publication: | 2014/12/02 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2015/07/23 |
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Tag: | LUBAC; Sharpin; TNFR1; apoptosis; cell biology; immunology; mouse; skin inflammation; ubiquitin |
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Volume: | 3 |
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Issue: | e03422 |
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Page Number: | 20 |
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First Page: | 1 |
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Last Page: | 20 |
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Note: | Copyright © 2014, Kumari et al This article is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ , which permits unrestricted use and redistribution provided that the original author and source are credited. |
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HeBIS-PPN: | 369743393 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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