Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis
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 o...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2014-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/03422 |
| _version_ | 1811180673942159360 |
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| author | Snehlata Kumari Younes Redouane Jaime Lopez-Mosqueda Ryoko Shiraishi Malgorzata Romanowska Stefan Lutzmayer Jan Kuiper Conception Martinez Ivan Dikic Manolis Pasparakis Fumiyo Ikeda |
| author_facet | Snehlata Kumari Younes Redouane Jaime Lopez-Mosqueda Ryoko Shiraishi Malgorzata Romanowska Stefan Lutzmayer Jan Kuiper Conception Martinez Ivan Dikic Manolis Pasparakis Fumiyo Ikeda |
| author_sort | Snehlata Kumari |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T09:07:03Z |
| format | Article |
| id | doaj.art-5400ea6fdffd423ba947794f3f1e0aa7 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:07:03Z |
| publishDate | 2014-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-5400ea6fdffd423ba947794f3f1e0aa72022-12-22T04:32:36ZengeLife Sciences Publications LtdeLife2050-084X2014-12-01310.7554/eLife.03422Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosisSnehlata Kumari0Younes Redouane1Jaime Lopez-Mosqueda2Ryoko Shiraishi3Malgorzata Romanowska4Stefan Lutzmayer5Jan Kuiper6Conception Martinez7Ivan Dikic8Manolis Pasparakis9Fumiyo Ikeda10Institute for Genetics, Center for Molecular Medicine, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, GermanyInstitute of Molecular Biotechnology, Vienna, AustriaInstitute of Biochemistry II, Goethe University Medical School, Frankfurt am Main, GermanyInstitute of Molecular Biotechnology, Vienna, AustriaInstitute for Genetics, Center for Molecular Medicine, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, GermanyInstitute of Molecular Biotechnology, Vienna, AustriaInstitute for Genetics, Center for Molecular Medicine, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, GermanyInstitute of Molecular Biotechnology, Vienna, AustriaInstitute of Biochemistry II, Goethe University Medical School, Frankfurt am Main, GermanyInstitute for Genetics, Center for Molecular Medicine, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, GermanyInstitute of Molecular Biotechnology, Vienna, AustriaLinear 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.https://elifesciences.org/articles/03422ubiquitinTNFR1Sharpinskin inflammationapoptosisLUBAC |
| spellingShingle | Snehlata Kumari Younes Redouane Jaime Lopez-Mosqueda Ryoko Shiraishi Malgorzata Romanowska Stefan Lutzmayer Jan Kuiper Conception Martinez Ivan Dikic Manolis Pasparakis Fumiyo Ikeda Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis eLife ubiquitin TNFR1 Sharpin skin inflammation apoptosis LUBAC |
| title | Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis |
| title_full | Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis |
| title_fullStr | Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis |
| title_full_unstemmed | Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis |
| title_short | Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis |
| title_sort | sharpin prevents skin inflammation by inhibiting tnfr1 induced keratinocyte apoptosis |
| topic | ubiquitin TNFR1 Sharpin skin inflammation apoptosis LUBAC |
| url | https://elifesciences.org/articles/03422 |
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