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Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis.

Kumari S, Redouane Y, Lopez-Mosqueda J, Shiraishi R, Romanowska M, Lutzmayer S, Kuiper J, Martinez C, Dikic I, Pasparakis M, Ikeda F - Elife (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genetics, Center for Molecular Medicine, University of Cologne, Cologne, Germany.

ABSTRACT
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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Cell death in the spleen of Sharpincpdm/cpdm, Sharpincpdm/cpdm; Tnfrsf1a−/−, Sharpincpdm/cpdm;TNFR1E-KO, Sharpincpdm/cpdm;Ripk3−/− and Sharpincpdm/cpdm;FADDE-KO;Ripk3−/− mice.(A and B) Cleaved caspase-3 (A) and TUNEL (B) staining on the spleen tissue sections from mice with the indicated genotypes between 12–18 weeks. The control mice compared were from the same breeding but not always littermates. Representative images are shown. The scale bars are 100 μm. Nuclei in (B) were visualized using DAPI.DOI:http://dx.doi.org/10.7554/eLife.03422.009
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fig5s1: Cell death in the spleen of Sharpincpdm/cpdm, Sharpincpdm/cpdm; Tnfrsf1a−/−, Sharpincpdm/cpdm;TNFR1E-KO, Sharpincpdm/cpdm;Ripk3−/− and Sharpincpdm/cpdm;FADDE-KO;Ripk3−/− mice.(A and B) Cleaved caspase-3 (A) and TUNEL (B) staining on the spleen tissue sections from mice with the indicated genotypes between 12–18 weeks. The control mice compared were from the same breeding but not always littermates. Representative images are shown. The scale bars are 100 μm. Nuclei in (B) were visualized using DAPI.DOI:http://dx.doi.org/10.7554/eLife.03422.009


Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis.

Kumari S, Redouane Y, Lopez-Mosqueda J, Shiraishi R, Romanowska M, Lutzmayer S, Kuiper J, Martinez C, Dikic I, Pasparakis M, Ikeda F - Elife (2014)

Cell death in the spleen of Sharpincpdm/cpdm, Sharpincpdm/cpdm; Tnfrsf1a−/−, Sharpincpdm/cpdm;TNFR1E-KO, Sharpincpdm/cpdm;Ripk3−/− and Sharpincpdm/cpdm;FADDE-KO;Ripk3−/− mice.(A and B) Cleaved caspase-3 (A) and TUNEL (B) staining on the spleen tissue sections from mice with the indicated genotypes between 12–18 weeks. The control mice compared were from the same breeding but not always littermates. Representative images are shown. The scale bars are 100 μm. Nuclei in (B) were visualized using DAPI.DOI:http://dx.doi.org/10.7554/eLife.03422.009
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4225491&req=5

fig5s1: Cell death in the spleen of Sharpincpdm/cpdm, Sharpincpdm/cpdm; Tnfrsf1a−/−, Sharpincpdm/cpdm;TNFR1E-KO, Sharpincpdm/cpdm;Ripk3−/− and Sharpincpdm/cpdm;FADDE-KO;Ripk3−/− mice.(A and B) Cleaved caspase-3 (A) and TUNEL (B) staining on the spleen tissue sections from mice with the indicated genotypes between 12–18 weeks. The control mice compared were from the same breeding but not always littermates. Representative images are shown. The scale bars are 100 μm. Nuclei in (B) were visualized using DAPI.DOI:http://dx.doi.org/10.7554/eLife.03422.009
Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genetics, Center for Molecular Medicine, University of Cologne, Cologne, Germany.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus