Linear ubiquitination prevents inflammation and regulates immune signalling
Open accessAbstract
Members of the tumour necrosis factor (TNF) receptor superfamily have important functions in immunity and inflammation. Recently linear ubiquitin chains assembled by a complex containing HOIL-1 and HOIP (also known as RBCK1 and RNF31, respectively) were implicated in TNF signalling, yet their relevance in vivo remained uncertain. Here we identify SHARPIN as a third component of the linear ubiquitin chain assembly complex, recruited to the CD40 and TNF receptor signalling complexes together with its other constituents, HOIL-1 and HOIP. Mass spectrometry of TNF signalling complexes revealed RIP1 (also known as RIPK1) and NEMO (also known as IKKγ or IKBKG) to be linearly ubiquitinated. Mutation of the Sharpin gene (Sharpin(cpdm/cpdm)) causes chronic proliferative dermatitis (cpdm) characterized by inflammatory skin lesions and defective lymphoid organogenesis. Gene induction by TNF, CD40 ligand and interleukin-1β was attenuated in cpdm-derived cells which were rendered sensitive to TNF-induced death. Importantly, Tnf gene deficiency prevented skin lesions in cpdm mice. We conclude that by enabling linear ubiquitination in the TNF receptor signalling complex, SHARPIN interferes with TNF-induced cell death and, thereby, prevents inflammation. Our results provide evidence for the relevance of linear ubiquitination in vivo in preventing inflammation and regulating immune signalling.
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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 Gerlach, Cordier 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 Gerlach et al., 2011
TNFR1 activation can have diverse outcomes depending on variables such as post-translational modification status of RIPK1, which impacts assembly of pro-survival vs pro-death signaling complexes.
“In particular, TNFR1 activation can have diverse outcomes depending on multiple variables, such as the post-translational modification status of RIPK1, which has a direct impact on the assembly of pro-survival vs. pro-death signaling complexes [323–325].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [325]
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“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.,…”
Background
- Authors
- Gerlach, B., Cordier, S. M., Schmukle, A. C., Emmerich, C. H., Rieser, E., Haas, T. L., Webb, A. I., Rickard, J. A., Anderton, H., Wong, W. W.-L., Nachbur, U., Gangoda, L., Warnken, U., Purcell, A. W., Silke, J., & Walczak, H.
- Affiliations
- German Cancer Research Center (DE)
- Imperial College London (GB)
- The University of Melbourne (AU)
- La Trobe University (AU)
- Corresponding author
- Walczak, Henning
- ORCID
- Venue
- Nature
- Published
- 2011-03
- Volume
- 471
- Issue
- 7340
- Pages
- 591-596
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2135332272
- Cited by
- 940
- References
- 0
- Citations by year
- 2026: 47 · 2025: 36 · 2024: 55 · 2023: 50 · 2022: 57 · 2021: 83 · 2020: 64 · 2019: 49 · 2018: 57 · 2017: 69 · 2016: 67 · 2015: 56 · 2014: 76 · 2013: 62 · 2012: 70
- FWCI
- 27.00
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Inflammation Research
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Cancer Research UK (10950)
- Biotechnology and Biological Sciences Research Council (BB/I004580/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- linear ubiquitination, SHARPIN, LUBAC, CD40 ligand, NF-κB activation, RIPK1, NEMO, HOIP, HOIL-1, inflammation, TNF-induced cell death, immune signaling
- MeSH terms
- Animals, Carrier Proteins, Cell Line, Humans, Immunity, Inflammation, Nerve Tissue Proteins, Phenotype, Skin, Transcription Factors, Tumor Necrosis Factor-alpha, Signal Transduction, NF-kappa B, Receptors, Tumor Necrosis Factor, CD40 Ligand, Ubiquitin, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases, Multiprotein Complexes, Mice, I-kappa B Kinase, Receptor-Interacting Protein Serine-Threonine Kinases, Interleukin-1beta, Ubiquitination
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