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SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex
Abstract
Cpdm (chronic proliferative dermatitis) mice develop chronic dermatitis and an immunodeficiency with increased serum IgM, 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). Spontaneous null mutations in the Sharpin (SHANK-associated RH domain interacting protein in postsynaptic density) gene are responsible for the cpdm phenotype in mice. SHARPIN shows significant similarity to HOIL-1L (also known as RBCK1), a component of linear ubiquitin chain assembly complex (LUBAC), which induces NF-κB activation through conjugation of linear polyubiquitin chains to NEMO. 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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“The most explored function of SHARPIN is its interaction with RBCK1 (HOIL) and RNF31 (HOIP) to form the Linear Ubiquitination Assembly Complex (LUBAC), a regulator of the canonical NF- κB pathway signalling”
From SHARPIN S146 phosphorylation mediates ARP2/3 interaction, cancer cell invasion and metastasis (2022) · cites this paper as Tokunaga, Nakagawa et al., 2011
Citations
Cites
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Involvement of linear polyubiquitylation of NEMO in NF-κB activation
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Self-citationA ubiquitin ligase complex assembles linear polyubiquitin chains
Kirisako, T., Kamei, K., Murata, S., Kato, M., Fukumoto, H., Kanie, M., Sano, S., Tokunaga, F., Tanaka, K., & Iwaï, K. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601360 · Cited by 803
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Ubiquitylation in innate and adaptive immunity
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Wächtershäuser, K. N., Schneider, J. V., Geßner, A., Andrieux, G., Kur, I.-M., Duschek, N., Weigert, A., Boerries, M., Rieger, M. A., Stelzer, E. H. K., et al. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02755-9 · Cited by 1
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Xu, J., Wang, R., Ding, L., Luo, Y., Gong, Y., Deng, Y., & Ren, T. (2026) · Clinical Rheumatology · doi:10.1007/s10067-026-08320-7
SHARPIN restrains IL-33 release by stromal cells to control ILC2 inflammation
Zeng, P., Mao, X., Zhang, W., Li, J., Wang, Z., Zhang, C., Li, Q., & Liu, Y. (2026) · Science Advances · doi:10.1126/sciadv.aea2388
RNF213 M1-ubiquitinates damaged mitochondria to activate pro-inflammatory NF-κB signalingPreprint
Heilig, R., Glover, H., Mellor, C. E. L., Cloix, C., McIlwraith, M. J., Flanagan, L., Paul, N. R., Thomason, P., Prasad, B., Ahmed, A., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.21.752888
Excess Met1-linked ubiquitination leads to solid aggregate formation
Kaypee, S., Miyasaka, M., NAKAJIMA, T., Nishimura, H., Sakamaki, J.-I., Komatsu, M., & Ikeda, F. (2026) · The EMBO Journal · doi:10.1038/s44318-026-00909-7 · Cited by 1
The binding of OTULIN restrains LUBAC activity to prevent TNF-driven immunopathology
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Atypical E3 ligase HOIL1 promotes MDA5 signaling and ester-linked ubiquitination of LGP2
Cheng, D., Zhu, J., Chathuranga, W. A. G., Chakraborty, S., Liu, G., Lacoursiere, R. E., Pruneda, J. N., Gack, M. U., & MacDuff, D. A. (2026) · mBio · doi:10.1128/mbio.02152-26 · Cited by 3
Ubiquitylation of unbranched glycogen and glycogenin-1 in branching enzyme-deficient cells
Morfin, V., Chen, L., Gourlay, R., Kelsall, I. R., & Cohen, P. (2026) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2026.154795
Metadata
- Authors
- Tokunaga, F., Nakagawa, T., Nakahara, M., Saeki, Y., Taniguchi, M., Sakata, S.-I., Tanaka, K., Nakano, H., & Iwai, K.
- Affiliations
- The University of Osaka (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Juntendo University (JP)
- Venue
- Nature
- Published
- 2011-03
- Volume
- 471
- Issue
- 7340
- Pages
- 633-636
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2001879129
- Cited by
- 609
- References
- 26
- Citations by year
- 2026: 21 · 2025: 17 · 2024: 30 · 2023: 22 · 2022: 41 · 2021: 57 · 2020: 35 · 2019: 38 · 2018: 39 · 2017: 43 · 2016: 46 · 2015: 42 · 2014: 46 · 2013: 42 · 2012: 57
- FWCI
- 19.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (23659404, 21000012, 23657075)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- SHARPIN, LUBAC, NF-κB activation, HOIL-1, HOIP, TNF signaling, CD40 ligand, ubiquitin conjugation, X-linked hyper-IgM syndrome, NEMO, immunodeficiency
- MeSH terms
- Animals, Carrier Proteins, Cells, Cultured, Humans, Nerve Tissue Proteins, Tumor Necrosis Factor-alpha, NF-kappa B, CD40 Ligand, Ubiquitin, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins, Mice, HEK293 Cells
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