Cited by 610NF-κB Signaling PathwaysUbiquitin and proteasome pathwaysImmune Response and Inflammation

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

Tokunaga, Fuminori, Nakagawa, Tomoko, Nakahara, Masaki, Saeki, Yasushi, Taniguchi, Masami, Sakata, Shin-ichi, Tanaka, Keiji, Nakano, Hiroyasu +1 more·2011·Nature

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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Crossref · 10.1038/nature09815

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  • SHARPIN interacts with RBCK1 (HOIL) and RNF31 (HOIP) to form LUBAC, a regulator of canonical NF-kB pathway signalling.

    “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

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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
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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