title: SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis.
abstract: 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.
authors: 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.
authors: Fumiyo
authors: F
authors: Ikeda
authors: Yonathan Lissanu
authors: YL
authors: Deribe
authors: Sigrid S
authors: SS
authors: Skånland
authors: Benjamin
authors: B
authors: Stieglitz
authors: Caroline
authors: C
authors: Grabbe
authors: Mirita
authors: M
authors: Franz-Wachtel
authors: Sjoerd J L
authors: SJ
authors: van Wijk
authors: Panchali
authors: P
authors: Goswami
authors: Vanja
authors: V
authors: Nagy
authors: Janos
authors: J
authors: Terzic
authors: Fuminori
authors: F
authors: Tokunaga
authors: Ariadne
authors: A
authors: Androulidaki
authors: Tomoko
authors: T
authors: Nakagawa
authors: Manolis
authors: M
authors: Pasparakis
authors: Kazuhiro
authors: K
authors: Iwai
authors: John P
authors: JP
authors: Sundberg
authors: Liliana
authors: L
authors: Schaefer
authors: Katrin
authors: K
authors: Rittinger
authors: Boris
authors: B
authors: Macek
authors: Ivan
authors: I
authors: Dikic
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002478:Cells, Cultured; D003872:Dermatitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D053181:Caspase 8; D053200:Fas-Associated Death Domain Protein; D051550:I-kappa B Kinase; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; C505534:Fadd protein, mouse; C514981:NEMO protein, mouse; C425287:sharpin; C492590:Rnf31 protein, mouse; C505526:Casp8 protein, mouse; C000607389:Rbck1 protein, mouse