TY - JOUR
T1 - SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis
AU - Ikeda, Fumiyo
AU - Deribe, Yonathan Lissanu
AU - Skånland, Sigrid S.
AU - Stieglitz, Benjamin
AU - Grabbe, Caroline
AU - Franz-Wachtel, Mirita
AU - Van Wijk, Sjoerd J.L.
AU - Goswami, Panchali
AU - Nagy, Vanja
AU - Terzic, Janos
AU - Tokunaga, Fuminori
AU - Androulidaki, Ariadne
AU - Nakagawa, Tomoko
AU - Pasparakis, Manolis
AU - Iwai, Kazuhiro
AU - Sundberg, John P.
AU - Schaefer, Liliana
AU - Rittinger, Katrin
AU - MacEk, Boris
AU - Dikic, Ivan
N1 - Funding Information:
Acknowledgements We thank E. Kim, K. Rajalingham and H.-J. Kreienkampfor reagents used in this study, I. Matic for initial MS analysis of HOIP/HOIL-1L samples, S. Wahl for sample preparation, and V. Dötsch and members of the Dikic lab for discussions and comments. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DI 931/3-1), the Cluster of Excellence ‘‘Macromolecular Complexes’’ of the Goethe University Frankfurt (EXC115) to I.D., Landesstiftung Baden-Württemberg to B.M., the Medical Research Council UK to K.R. and B.S., JSPS Postdoctoral Fellowships for Research Abroad to F.I., EMBO long-term fellowship to S.S.S.andTheNationalInstitutes of Health(AR049288 toJ.P.S.). V.N.was supported by the Unity Through Knowledge Fund, 3B Grant. C.G. acknowledges support from The International Human Frontier Science Program Organization.
PY - 2011/3/31
Y1 - 2011/3/31
N2 - 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 Iβ°B kinases (IKKs) and subsequent activation of NF-β°B 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.
AB - 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 Iβ°B kinases (IKKs) and subsequent activation of NF-β°B 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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U2 - 10.1038/nature09814
DO - 10.1038/nature09814
M3 - Article
C2 - 21455181
AN - SCOPUS:79953239980
SN - 0028-0836
VL - 471
SP - 637
EP - 641
JO - Nature
JF - Nature
IS - 7340
ER -