| SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. | |
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MedLine Citation:
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PMID: 21455181 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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SHARPIN is a ubiquitin-binding and ubiquitin-like-domain-containing protein which, when mutated in mice, results in immune system disorders and multi-organ inflammation. Here we report that SHARPIN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) and that the absence of SHARPIN causes dysregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis (cpdm) in SHARPIN-deficient mice. Upon binding to the LUBAC subunit HOIP (also known as RNF31), SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Coexpression of SHARPIN and HOIP promotes linear ubiquitination of NEMO (also known as IKBKG), an adaptor of the IκB kinases (IKKs) and subsequent activation of NF-κB signalling, whereas SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-κB in B cells, macrophages and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L (also known as RBCK1), another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon tumour-necrosis factor α (TNF-α) stimulation via FADD- and caspase-8-dependent pathways. SHARPIN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo. |
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Authors:
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Fumiyo Ikeda; Yonathan Lissanu Deribe; Sigrid S Skånland; Benjamin Stieglitz; Caroline Grabbe; Mirita Franz-Wachtel; Sjoerd J L van Wijk; Panchali Goswami; Vanja Nagy; Janos Terzic; Fuminori Tokunaga; Ariadne Androulidaki; Tomoko Nakagawa; Manolis Pasparakis; Kazuhiro Iwai; John P Sundberg; Liliana Schaefer; Katrin Rittinger; Boris Macek; Ivan Dikic |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Nature Volume: 471 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-04-01 Completed Date: 2011-05-25 Revised Date: 2012-04-04 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 637-41 Citation Subset: IM |
Affiliation:
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Frankfurt Institute for Molecular Life Sciences and Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt, Main, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis* / drug effects B-Lymphocytes / metabolism Carrier Proteins / metabolism Caspase 8 / metabolism Cells, Cultured Dermatitis / genetics, metabolism, pathology Fas-Associated Death Domain Protein / metabolism Fibroblasts / metabolism HEK293 Cells HeLa Cells Humans I-kappa B Kinase / metabolism Intracellular Signaling Peptides and Proteins / metabolism Macrophages / metabolism Mice NF-kappa B / metabolism* Nerve Tissue Proteins / deficiency, genetics, metabolism* Tumor Necrosis Factor-alpha / metabolism, pharmacology Ubiquitin / metabolism* Ubiquitin-Protein Ligase Complexes / metabolism* Ubiquitin-Protein Ligases / metabolism Ubiquitination |
| Grant Support | |
ID/Acronym/Agency:
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AR049288/AR/NIAMS NIH HHS; R01 AR049288-07/AR/NIAMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Carrier Proteins; 0/Fadd protein, mouse; 0/Fas-Associated Death Domain Protein; 0/HOIL-1L protein, mouse; 0/Intracellular Signaling Peptides and Proteins; 0/NEMO protein, mouse; 0/NF-kappa B; 0/Nerve Tissue Proteins; 0/Tumor Necrosis Factor-alpha; 0/Ubiquitin; 0/sharpin; EC 2.7.11.10/I-kappa B Kinase; EC 3.4.22.-/Casp8 protein, mouse; EC 3.4.22.-/Caspase 8; EC 6.3.2.19/PAUL protein, mouse; EC 6.3.2.19/Ubiquitin-Protein Ligase Complexes; EC 6.3.2.19/Ubiquitin-Protein Ligases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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