SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex - Nature
- ️Iwai, Kazuhiro
- ️Wed Mar 30 2011
- Letter
- Published: 30 March 2011
Nature volume 471, pages 633–636 (2011)Cite this article
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Abstract
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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Acknowledgements
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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Fuminori Tokunaga and Tomoko Nakagawa: These authors contributed equally to this work.
Authors and Affiliations
Department of Biophysics and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan,
Fuminori Tokunaga, Tomoko Nakagawa, Masaki Nakahara, Masami Taniguchi, Shin-ichi Sakata & Kazuhiro Iwai
Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan,
Yasushi Saeki & Keiji Tanaka
Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan,
Hiroyasu Nakano
Cell Biology and Metabolism Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan,
Kazuhiro Iwai
Authors
- Fuminori Tokunaga
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- Tomoko Nakagawa
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- Masaki Nakahara
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- Yasushi Saeki
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- Masami Taniguchi
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- Shin-ichi Sakata
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- Keiji Tanaka
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- Hiroyasu Nakano
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- Kazuhiro Iwai
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Contributions
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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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). https://doi.org/10.1038/nature09815
Received: 25 January 2010
Accepted: 11 January 2011
Published: 30 March 2011
Issue Date: 31 March 2011
DOI: https://doi.org/10.1038/nature09815
Editorial Summary
SHARPIN protein role in immune signalling
The ubiquitin conjugation system regulates the canonical (or classical) nuclear factor κB (NF-κB)-activation pathway that mediates immune responses. Linear polyubiquitin chains, in which the C-terminal glycine of ubiquitin is conjugated to the amino group of the N-terminal methionine of another ubiquitin, is generated by a unique ubiquitin ligase complex called LUBAC — the linear ubiquitin chain assembly complex. LUBAC is composed of two RING domain proteins called HOIL-1 and HOIP. Now, three complementary studies published by the laboratories of Henning Walczak, Kazuhiro Iwai and Ivan Dikic identify a novel component of the LUBAC complex called SHARPIN, which is recruited to receptor signalling complexes that form following TNF and CD40L stimulation. The LUBAC complex containing SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo and is required for the activation of NF-κB signalling.