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SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex


Cpdm (chronic proliferative dermatitis) mice develop chronic dermatitis and an immunodeficiency with increased serum IgM1,2,3, symptoms that resemble those of patients with X-linked hyper-IgM syndrome and hypohydrotic ectodermal dysplasia (XHM-ED), which is caused by mutations in NEMO (NF-κB essential modulator; also known as IKBKG)4,5,6. Spontaneous null mutations in the Sharpin (SHANK-associated RH domain interacting protein in postsynaptic density)7 gene are responsible for the cpdm phenotype in mice8. SHARPIN shows significant similarity to HOIL-1L (also known as RBCK1)8,9, a component of linear ubiquitin chain assembly complex (LUBAC), which induces NF-κB activation through conjugation of linear polyubiquitin chains to NEMO10,11,12,13. Here, we identify SHARPIN as an additional component of LUBAC. SHARPIN-containing complexes can linearly ubiquitinate NEMO and activated NF-κB. Thus, we re-define LUBAC as a complex containing SHARPIN, HOIL-1L, and HOIP (also known as RNF31). Deletion of SHARPIN drastically reduced the amount of LUBAC, which resulted in attenuated TNF-α- and CD40-mediated activation of NF-κB in mouse embryonic fibroblasts (MEFs) or B cells from cpdm mice. Considering the pleomorphic phenotype of cpdm mice, these results confirm the predicted role of LUBAC-mediated linear polyubiquitination in NF-κB activation induced by various stimuli, and strongly suggest the involvement of LUBAC-induced NF-κB activation in various disorders.

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Figure 1: Ablation of Sharpin causes impaired NF-κB signalling.
Figure 2: Linear-ubiquitination of NEMO by SHARPIN-containing LUBAC activates NF-κB.
Figure 3: SHARPIN affects the stability of LUBAC.
Figure 4: Involvement of LUBAC in NF-κB activation induced by various stimuli.


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We thank T. Kitamura, S. Sugano, P. Rennert and J. Browning for reagents; O. Takeuchi for comments; and K. Kamei and K. Fukunaga for technical assistance. This work was partly supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (F.T. and K.I.).

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F.T., T.N., M.N., Y.S, M.T., S.-i.S. and H.N. performed experiments. K.T. and K.I. coordinated the study, and F.T. and K.I. wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Kazuhiro Iwai.

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The authors declare no competing financial interests.

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Tokunaga, F., Nakagawa, T., Nakahara, M. et al. SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex. Nature 471, 633–636 (2011).

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