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Cited by 745NF-κB Signaling PathwaysUbiquitin and proteasome pathwaysImmune Response and Inflammation

SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis

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Ikeda, Fumiyo, Deribe, Yonathan Lissanu, Skånland, Sigrid S., Stieglitz, Benjamin, Grabbe, Caroline, Franz-Wachtel, Mirita, van Wijk, Sjoerd J. L., Goswami, Panchali +12 more·2011·Nature
DOI 10.1038/nature09814PMC PMC3085511
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Abstract

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 IκB kinases (IKKs) and subsequent activation of NF-κB 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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  • 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 Ikeda, Deribe et al., 2011

  • SHARPIN is a multifunctional protein regulating a number of cellular pathways and functions.

    “SHARPIN is a multifunctional protein regulating a number of cellular pathways and functions (Gerlach et al., 2011, He et al., 2010, Ikeda et al., 2011, Landgraf et al., 2010, Lim et al., 2001, Nastase et al., 2016, Park et al., 2016, Pouwels et al., 2013, Rantala et al., 2011, Tokunaga et al., 2011)”

    From SHARPIN S146 phosphorylation mediates ARP2/3 interaction, cancer cell invasion and metastasis (2022) · cites this paper as Ikeda et al., 2011

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Research works printed but not linked: 25

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Authors
Ikeda, F., Deribe, Y. L., Skånland, S. S., Stieglitz, B., Grabbe, C., Franz-Wachtel, M., van Wijk, S. J. L., Goswami, P., Nagy, V., Terzic, J., Tokunaga, F., Androulidaki, A., Nakagawa, T., Pasparakis, M., Iwai, K., Sundberg, J. P., Schaefer, L., Rittinger, K., Macek, B., & Dikic, I.
Affiliations
  • Goethe University Frankfurt (DE)
  • National Institute for Medical Research (GB)
  • Institute of Molecular Biotechnology (AT)
  • The University of Osaka (JP)
  • University of Cologne (DE)
  • Jackson Laboratory (US)
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2011-03
Volume
471
Issue
7340
Pages
637-641
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature09814
PMC
PMC3085511
OpenAlex
W2032195857
Cited by
745
References
2
Citations by year
2026: 30 · 2025: 26 · 2024: 36 · 2023: 36 · 2022: 49 · 2021: 71 · 2020: 41 · 2019: 44 · 2018: 44 · 2017: 56 · 2016: 55 · 2015: 48 · 2014: 61 · 2013: 50 · 2012: 61
FWCI
22.42
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
Funders
  • Japan Society for the Promotion of Science (23657075)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR049288, AR049288)
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, HOIP, RNF31, HOIL-1, ubiquitin ligase, TNF signaling, CD40 ligand, apoptosis, immune regulation, inflammation
MeSH terms
Animals, B-Lymphocytes, Carrier Proteins, Cells, Cultured, Dermatitis, Fibroblasts, HeLa Cells, Humans, Macrophages, Nerve Tissue Proteins, Tumor Necrosis Factor-alpha, NF-kappa B, Apoptosis, Ubiquitin, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases, Intracellular Signaling Peptides and Proteins, Mice, I-kappa B Kinase, Caspase 8, Fas-Associated Death Domain Protein, Ubiquitination, HEK293 Cells

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