Publication Date:
2011-04-02
Description:
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-kappaB 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 IkappaB kinases (IKKs) and subsequent activation of NF-kappaB signalling, whereas SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-kappaB 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 alpha (TNF-alpha) stimulation via FADD- and caspase-8-dependent pathways. SHARPIN thus activates NF-kappaB and inhibits apoptosis via distinct pathways in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085511/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085511/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ikeda, Fumiyo -- Deribe, Yonathan Lissanu -- Skanland, Sigrid S -- Stieglitz, Benjamin -- Grabbe, Caroline -- Franz-Wachtel, Mirita -- van Wijk, Sjoerd J L -- Goswami, Panchali -- Nagy, Vanja -- Terzic, Janos -- Tokunaga, Fuminori -- Androulidaki, Ariadne -- Nakagawa, Tomoko -- Pasparakis, Manolis -- Iwai, Kazuhiro -- Sundberg, John P -- Schaefer, Liliana -- Rittinger, Katrin -- Macek, Boris -- Dikic, Ivan -- AR049288/AR/NIAMS NIH HHS/ -- MC_U117565398/Medical Research Council/United Kingdom -- R01 AR049288/AR/NIAMS NIH HHS/ -- R01 AR049288-07/AR/NIAMS NIH HHS/ -- England -- Nature. 2011 Mar 31;471(7340):637-41. doi: 10.1038/nature09814.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21455181" target="_blank"〉PubMed〈/a〉
Keywords:
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
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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