Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency.
Journal
Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354
Informations de publication
Date de publication:
12 Apr 2024
12 Apr 2024
Historique:
received:
29
11
2022
accepted:
14
03
2024
medline:
13
4
2024
pubmed:
13
4
2024
entrez:
12
4
2024
Statut:
aheadofprint
Résumé
The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.
Identifiants
pubmed: 38609546
doi: 10.1038/s41590-024-01817-w
pii: 10.1038/s41590-024-01817-w
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 414786233
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 390661388
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 413326622
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 455784452
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 414786233
Organisme : Fritz Thyssen Stiftung (Fritz Thyssen Foundation)
ID : 10.23.1.013MN
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 1194144
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 1195038
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 2017929
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : GNT9000719
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-11-LABX-0070_TRANSPLANTEX
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-10-IDEX-0002
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-20-SFRI-0012
Organisme : Cancer Research UK (CRUK)
ID : A27323
Organisme : Wellcome Trust (Wellcome)
ID : 214342/Z/18/Z
Organisme : RCUK | Medical Research Council (MRC)
ID : MR/S00811X/1
Informations de copyright
© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
Références
Iwai, K., Fujita, H. & Sasaki, Y. Linear ubiquitin chains: NF-κB signalling, cell death and beyond. Nat. Rev. Mol. Cell Biol. 15, 503–508 (2014).
pubmed: 25027653
doi: 10.1038/nrm3836
Fuseya, Y. et al. The HOIL-1L ligase modulates immune signalling and cell death via monoubiquitination of LUBAC. Nat. Cell Biol. 22, 663–673 (2020).
pubmed: 32393887
doi: 10.1038/s41556-020-0517-9
Kelsall, I. R., Zhang, J., Knebel, A., Arthur, J. S. C. & Cohen, P. The E3 ligase HOIL-1 catalyses ester bond formation between ubiquitin and components of the Myddosome in mammalian cells. Proc. Natl Acad. Sci. USA 116, 13293–13298 (2019).
pubmed: 31209050
pmcid: 6613137
doi: 10.1073/pnas.1905873116
Boisson, B. et al. Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. J. Exp. Med. 212, 939–951 (2015).
pubmed: 26008899
pmcid: 4451137
doi: 10.1084/jem.20141130
Boisson, B. et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat. Immunol. 13, 1178–1186 (2012).
pubmed: 23104095
pmcid: 3514453
doi: 10.1038/ni.2457
Oda, H. et al. Second case of HOIP deficiency expands clinical features and defines inflammatory transcriptome regulated by LUBAC. Front. Immunol. 10, 479 (2019).
pubmed: 30936877
pmcid: 6431612
doi: 10.3389/fimmu.2019.00479
Peltzer, N. et al. LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis. Nature 557, 112–117 (2018).
pubmed: 29695863
pmcid: 5947819
doi: 10.1038/s41586-018-0064-8
Peltzer, N. et al. HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death. Cell Rep. 9, 153–165 (2014).
pubmed: 25284787
doi: 10.1016/j.celrep.2014.08.066
HogenEsch, H. et al. A spontaneous mutation characterized by chronic proliferative dermatitis in C57BL mice. Am. J. Pathol. 143, 972–982 (1993).
pubmed: 8362989
pmcid: 1887192
Gerlach, B. et al. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471, 591–596 (2011).
pubmed: 21455173
doi: 10.1038/nature09816
Ikeda, F. et al. SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. Nature 471, 637–641 (2011).
pubmed: 21455181
pmcid: 3085511
doi: 10.1038/nature09814
Kumari, S. et al. SHARPIN prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis. eLife 3, e03422 (2014).
Rickard, J. A. et al. TNFR1-dependent cell death drives inflammation in SHARPIN-deficient mice. eLife 3, e03464 (2014).
Tokunaga, F. et al. SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex. Nature 471, 633–636 (2011).
pubmed: 21455180
doi: 10.1038/nature09815
Lafont, E. et al. TBK1 and IKKε prevent TNF-induced cell death by RIPK1 phosphorylation. Nat. Cell Biol. 20, 1389–1399 (2018).
pubmed: 30420664
pmcid: 6268100
doi: 10.1038/s41556-018-0229-6
Sasaki, Y. et al. Defective immune responses in mice lacking LUBAC-mediated linear ubiquitination in B cells. EMBO J. 32, 2463–2476 (2013).
pubmed: 23942237
pmcid: 3770953
doi: 10.1038/emboj.2013.184
Draber, P. et al. LUBAC-recruited CYLD and A20 regulate gene activation and cell death by exerting opposing effects on linear ubiquitin in signaling complexes. Cell Rep. 13, 2258–2272 (2015).
pubmed: 26670046
pmcid: 4688036
doi: 10.1016/j.celrep.2015.11.009
Vince, J. E. et al. IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis. Cell 131, 682–693 (2007).
pubmed: 18022363
doi: 10.1016/j.cell.2007.10.037
de Almagro, M. C., Goncharov, T., Newton, K. & Vucic, D. Cellular IAP proteins and LUBAC differentially regulate necrosome-associated RIP1 ubiquitination. Cell Death Dis. 6, e1800 (2015).
pubmed: 26111062
pmcid: 4669837
doi: 10.1038/cddis.2015.158
Laurien, L. et al. Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation. Nat. Commun. 11, 1747 (2020).
pubmed: 32269263
pmcid: 7142081
doi: 10.1038/s41467-020-15466-8
Kay, J. & Calabrese, L. The role of interleukin-1 in the pathogenesis of rheumatoid arthritis. Rheumatology 43, iii2–iii9 (2004).
pubmed: 15150426
doi: 10.1093/rheumatology/keh201
Wijbrandts, C. A. et al. The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor alpha expression in the synovium. Ann. Rheum. Dis. 67, 1139–1144 (2008).
pubmed: 18055470
doi: 10.1136/ard.2007.080440
Sundberg, J. P. et al. Keratinocyte-specific deletion of SHARPIN induces atopic dermatitis-like inflammation in mice. PLoS ONE 15, e0235295 (2020).
pubmed: 32687504
pmcid: 7371178
doi: 10.1371/journal.pone.0235295
Wang, J. et al. LUBAC suppresses IL-21-induced apoptosis in CD40-activated murine B cells and promotes germinal center B cell survival and the T-dependent antibody response. Front. Immunol. 12, 658048 (2021).
pubmed: 33953720
pmcid: 8089397
doi: 10.3389/fimmu.2021.658048
Roco, J. A. et al. Class-switch recombination occurs infrequently in germinal centers. Immunity 51, 337–350 (2019).
pubmed: 31375460
pmcid: 6914312
doi: 10.1016/j.immuni.2019.07.001
Elsner, R. A. & Shlomchik, M. J. Germinal center and extrafollicular B cell responses in vaccination, immunity, and autoimmunity. Immunity 53, 1136–1150 (2020).
pubmed: 33326765
pmcid: 7748291
doi: 10.1016/j.immuni.2020.11.006
Teh, C. E. et al. Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis. Nat. Commun. 7, 13353 (2016).
pubmed: 27857075
pmcid: 5120208
doi: 10.1038/ncomms13353
Park, Y. et al. SHARPIN controls regulatory T cells by negatively modulating the T cell antigen receptor complex. Nat. Immunol. 17, 286–296 (2016).
pubmed: 26829767
pmcid: 4919114
doi: 10.1038/ni.3352
HogenEsch, H. et al. Increased expression of type 2 cytokines in chronic proliferative dermatitis (cpdm) mutant mice and resolution of inflammation following treatment with IL-12. Eur. J. Immunol. 31, 734–742 (2001).
pubmed: 11241277
doi: 10.1002/1521-4141(200103)31:3<734::AID-IMMU734>3.0.CO;2-9
van Zelm, M. C. et al. Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation. J. Allergy Clin. Immunol. 134, 135–144 (2014).
pubmed: 24418477
doi: 10.1016/j.jaci.2013.11.015
Meyers, G. et al. Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans. Proc. Natl Acad. Sci. USA 108, 11554–11559 (2011).
pubmed: 21700883
pmcid: 3136251
doi: 10.1073/pnas.1102600108
McGowan, H. W. et al. Sharpin is a key regulator of skeletal homeostasis in a TNF-dependent manner. J. Musculoskelet. Neuronal Interact. 14, 454–463 (2014).
pubmed: 25524971
Kim, H. et al. Development of a validated interferon score using NanoString technology. J. Interferon Cytokine Res. 38, 171–185 (2018).
pubmed: 29638206
pmcid: 5963606
doi: 10.1089/jir.2017.0127
Panayotova-Dimitrova, D. et al. cFLIP regulates skin homeostasis and protects against TNF-induced keratinocyte apoptosis. Cell Rep. 5, 397–408 (2013).
pubmed: 24209745
doi: 10.1016/j.celrep.2013.09.035
Weinlich, R. et al. Protective roles for caspase-8 and cFLIP in adult homeostasis. Cell Rep. 5, 340–348 (2013).
pubmed: 24095739
doi: 10.1016/j.celrep.2013.08.045
Orning, P. et al. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science 362, 1064–1069 (2018).
pubmed: 30361383
pmcid: 6522129
doi: 10.1126/science.aau2818
Sarhan, J. et al. Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. Proc. Natl Acad. Sci. USA 115, E10888–E10897 (2018).
pubmed: 30381458
pmcid: 6243247
doi: 10.1073/pnas.1809548115
Gurung, P., Lamkanfi, M. & Kanneganti, T. D. Cutting edge: SHARPIN is required for optimal NLRP3 inflammasome activation. J. Immunol. 194, 2064–2067 (2015).
pubmed: 25637014
doi: 10.4049/jimmunol.1402951
Douglas, T., Champagne, C., Morizot, A., Lapointe, J. M. & Saleh, M. The inflammatory caspases-1 and -11 mediate the pathogenesis of dermatitis in SHARPIN-deficient mice. J. Immunol. 195, 2365–2373 (2015).
pubmed: 26216893
doi: 10.4049/jimmunol.1500542
Gurung, P., Sharma, B. R. & Kanneganti, T. D. Distinct role of IL-1β in instigating disease in Sharpin(cpdm) mice. Sci. Rep. 6, 36634 (2016).
pubmed: 27892465
pmcid: 5125001
doi: 10.1038/srep36634
Anderton, H. et al. Langerhans cells are an essential cellular intermediary in chronic dermatitis. Cell Rep. 39, 110922 (2022).
pubmed: 35675765
doi: 10.1016/j.celrep.2022.110922
Anderton, H., Wicks, I. P. & Silke, J. Cell death in chronic inflammation: breaking the cycle to treat rheumatic disease. Nat. Rev. Rheumatol. 16, 496–513 (2020).
pubmed: 32641743
doi: 10.1038/s41584-020-0455-8
van Loo, G. & Bertrand, M. J. M. Death by TNF: a road to inflammation. Nat. Rev. Immunol. 23, 289–303 (2023).
pubmed: 36380021
doi: 10.1038/s41577-022-00792-3
Pasparakis, M. & Vandenabeele, P. Necroptosis and its role in inflammation. Nature 517, 311–320 (2015).
pubmed: 25592536
doi: 10.1038/nature14191
Mifflin, L., Ofengeim, D. & Yuan, J. Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target. Nat. Rev. Drug Discov. 19, 553–571 (2020).
pubmed: 32669658
pmcid: 7362612
doi: 10.1038/s41573-020-0071-y
Weisel, K. et al. A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis. Arthritis Res. Ther. 23, 85 (2021).
pubmed: 33726834
pmcid: 7962407
doi: 10.1186/s13075-021-02468-0
Weisel, K. et al. A randomised, placebo-controlled study of RIPK1 inhibitor GSK2982772 in patients with active ulcerative colitis. BMJ Open Gastroenterol. 8, e000680 (2021).
Lalaoui, N. et al. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature 577, 103–108 (2020).
pubmed: 31827281
doi: 10.1038/s41586-019-1828-5
Tao, P. et al. A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1. Nature 577, 109–114 (2020).
pubmed: 31827280
doi: 10.1038/s41586-019-1830-y
Cuchet-Lourenco, D. et al. Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science 361, 810–813 (2018).
pubmed: 30026316
pmcid: 6529353
doi: 10.1126/science.aar2641
Li, Y. et al. Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 116, 970–975 (2019).
pubmed: 30591564
doi: 10.1073/pnas.1813582116
Taft, J. et al. Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death. Cell 184, 4447–4463 (2021).
pubmed: 34363755
pmcid: 8380741
doi: 10.1016/j.cell.2021.07.026
Badran, Y. R. et al. Human RELA haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration. J. Exp. Med. 214, 1937–1947 (2017).
pubmed: 28600438
pmcid: 5502421
doi: 10.1084/jem.20160724
Damgaard, R. B. et al. OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death. EMBO Mol. Med. 11, e9324 (2019).
Zinngrebe, J. et al. LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation. J. Exp. Med. 213, 2671–2689 (2016).
pubmed: 27810922
pmcid: 5110014
doi: 10.1084/jem.20160041
Kelsall, I. R. et al. HOIL-1 ubiquitin ligase activity targets unbranched glucosaccharides and is required to prevent polyglucosan accumulation. EMBO J. 41, e109700 (2022).
pubmed: 35274759
pmcid: 9016349
doi: 10.15252/embj.2021109700
Otten, E. G. et al. Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection. Nature 594, 111–116 (2021).
pubmed: 34012115
pmcid: 7610904
doi: 10.1038/s41586-021-03566-4
Matsumoto, M. L. et al. Engineering and structural characterization of a linear polyubiquitin-specific antibody. J. Mol. Biol. 418, 134–144 (2012).
pubmed: 22227388
doi: 10.1016/j.jmb.2011.12.053
Zinngrebe, J. et al. Compound heterozygous variants in OTULIN are associated with fulminant atypical late-onset ORAS. EMBO Mol. Med. 14, e14901 (2022).
pubmed: 35170849
pmcid: 8899767
doi: 10.15252/emmm.202114901
Samson, A. L. et al. A toolbox for imaging RIPK1, RIPK3, and MLKL in mouse and human cells. Cell Death Differ. 28, 2126–2144 (2021).
pubmed: 33589776
pmcid: 8257593
doi: 10.1038/s41418-021-00742-x
Wang, K. et al. Structural mechanism for GSDMD targeting by autoprocessed caspases in pyroptosis. Cell 180, 941–955 (2020).
pubmed: 32109412
doi: 10.1016/j.cell.2020.02.002