Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis

Snehlata Kumari, Younes Redouane, Jaime Lopez-Mosqueda, Ryoko Shiraishi, Malgorzata Romanowska, Stefan Lutzmayer, Jan Kuiper, Conception Martinez, Ivan Dikic, Manolis Pasparakis, Fumiyo Ikeda

Research output: Contribution to journalArticle

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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.

Original languageEnglish
JournaleLife
Volume3
DOIs
Publication statusPublished - Jan 1 2014

Fingerprint

Tumor Necrosis Factor Receptors
Fas-Associated Death Domain Protein
Keratinocytes
Skin
Apoptosis
Receptors, Tumor Necrosis Factor, Type I
Inflammation
Ubiquitin
Receptor-Interacting Protein Serine-Threonine Kinases
Tumor Necrosis Factor-alpha
Protein Kinases
Proteins
Ubiquitin-Protein Ligases
Fibroblasts
Ablation
Epidermis
sharpin
Chemical activation
Death Domain

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Kumari, S., Redouane, Y., Lopez-Mosqueda, J., Shiraishi, R., Romanowska, M., Lutzmayer, S., ... Ikeda, F. (2014). Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis. eLife, 3. https://doi.org/10.7554/eLife.03422

Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis. / Kumari, Snehlata; Redouane, Younes; Lopez-Mosqueda, Jaime; Shiraishi, Ryoko; Romanowska, Malgorzata; Lutzmayer, Stefan; Kuiper, Jan; Martinez, Conception; Dikic, Ivan; Pasparakis, Manolis; Ikeda, Fumiyo.

In: eLife, Vol. 3, 01.01.2014.

Research output: Contribution to journalArticle

Kumari, S, Redouane, Y, Lopez-Mosqueda, J, Shiraishi, R, Romanowska, M, Lutzmayer, S, Kuiper, J, Martinez, C, Dikic, I, Pasparakis, M & Ikeda, F 2014, 'Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis', eLife, vol. 3. https://doi.org/10.7554/eLife.03422
Kumari S, Redouane Y, Lopez-Mosqueda J, Shiraishi R, Romanowska M, Lutzmayer S et al. Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis. eLife. 2014 Jan 1;3. https://doi.org/10.7554/eLife.03422
Kumari, Snehlata ; Redouane, Younes ; Lopez-Mosqueda, Jaime ; Shiraishi, Ryoko ; Romanowska, Malgorzata ; Lutzmayer, Stefan ; Kuiper, Jan ; Martinez, Conception ; Dikic, Ivan ; Pasparakis, Manolis ; Ikeda, Fumiyo. / Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis. In: eLife. 2014 ; Vol. 3.
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