Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease

Zhou, Qing; Wang, Hongying; Schwartz, Daniella M.; Stoffels, Monique; Park, Yong Hwan; Zhang, Yuan; Yang, Dan; Demirkaya, Erkan; Takeuchi, Masaki; Tsai, Wanxia Li; Lyons, Jonathan J.; Yu, Xiaomin; Ouyang, Claudia; Chen, Celeste; Chin, David A.; Zaal, Kristien J.M.; Chandrasekharappa, Settara C.; Hanson, Eric P.; Yu, Zhen; Mullikin, James C.; Hasni, Sarfaraz; Wertz, Ingrid E.; Ombrello, Amanda K.; Stone, Deborah L.; Hoffmann, Patrycja; Jones, Anne; Barham, Beverly; Leavis, Helen L.; Royen-Kerkof, Annet Van; Sibley, Cailin H.; Batu, Ezgi Deniz; Gül, Ahmet; Siegel, Richard M.; Boehm, Manfred; Milner, Joshua D.; Özen, Seza; Gadina, Massimo; Chae, Jae Jin; Laxer, Ronald M.; Kastner, Daniel L.; Aksentijevich, Ivona

doi:10.1038/ng.3459

Cited by 520 publications

(538 citation statements)

References 48 publications

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“…TNFAIP3 SNPs that in some cases function to reduce A20 expression levels have been identified that confer susceptibility to rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and Behçets disease (37)(38)(39)(40). A recently described familial syndrome with reduced A20 function as a result of haploinsufficiency exhibits inflammatory disease phenotypes that are similar to those with ΔCT-NEMO mutation (41). Therefore, our findings underscore the functional importance of A20 in preventing inflammatory disease in humans.…”

Section: Discussionsupporting

confidence: 50%

Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease

Zilberman‐Rudenko

Shawver

Wessel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Receptor-induced NF-κB activation is controlled by NEMO, the NF-κB essential modulator. Hypomorphic NEMO mutations result in X-linked ectodermal dysplasia with anhidrosis and immunodeficiency, also referred to as NEMO syndrome. Here we describe a distinct group of patients with NEMO C-terminal deletion (ΔCT-NEMO) mutations. Individuals harboring these mutations develop inflammatory skin and intestinal disease in addition to ectodermal dysplasia with anhidrosis and immunodeficiency. Both primary cells from these patients, as well as reconstituted cell lines with this deletion, exhibited increased IκB kinase (IKK) activity and production of proinflammatory cytokines. Unlike previously described loss-of-function mutations, ΔCT-NEMO mutants promoted increased NF-κB activation in response to TNF and Toll-like receptor stimulation. Investigation of the underlying mechanisms revealed impaired interactions with A20, a negative regulator of NF-κB activation, leading to prolonged accumulation of K63-ubiquitinated RIP within the TNFR1 signaling complex. Recruitment of A20 to the C-terminal domain of NEMO represents a novel mechanism limiting NF-κB activation by NEMO, and its absence results in autoinflammatory disease.ctivation of the NF-κB family of transcription factors is required for normal development, innate and adaptive immunity, and the inflammatory response (1, 2). NF-κB-induced transcription of proinflammatory cytokines and chemokines amplifies immune-response programs and stimulates recruitment of inflammatory cells. Transcriptional activity of the classic NF-κB p65/p50 complex is regulated by the inhibitor of NF-κB kinase (IKK), consisting of the α-and β-catalytic subunits and the NEMO (NF-κB essential modulator, IKKγ) regulatory subunit. IKK activity leads to phosphorylation and K48-linked polyubiquitination of IκBα, the inhibitor of NF-κB. Ubiquitinated IκBα is then rapidly degraded, allowing nuclear translocation of NF-κB subunits and gene transactivation. NEMO functions as a scaffold within the IKK complex that is required for canonical IKK enzymatic activity and NF-κB activation (3).Activation of TNF, IL-1R, and Toll-like receptor (TLR) family receptors leads to K63 and linear (also termed M1) ubiquitination of cytosolic adapter proteins, such as receptor interacting protein 1 (RIP1). This in turn promotes recruitment of the IKK complex to the receptor signaling complex (4-8). A well-known negative regulator of NF-κB activation is A20 (encoded by the gene TNFAIP3). In the TNF-R1 complex, A20 removes K63-linked ubiquitin modifications on RIP1 through its deubiquitinase activity and converts these to K48-linked polyubiquitin chains through its E3 ligase activity (9). Editing of polyubiquitin linkages at the receptor complex in this manner results in rapid degradation of RIP1 and other signaling proteins, such as TRAF6, TRAF2, cIAP1, and cIAP2 (9, 10), promoting the termination of receptor-induced NF-κB activation. In addition, A20 directly inhibits IKK activity independently of its deubiquitinase activity in...

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Section: Discussionsupporting

confidence: 50%

Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease

Zilberman‐Rudenko

Shawver

Wessel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…This is the second report of human germline mutations in a deubiquitinase protein leading to an inflammatory phenotype, the first being mutations in DUB A20 (10). In contrast, deficiency of another deubiquitinase CYLD, which hydrolyzes both Met1 and K63 ubiquitin chains, leads to cylindromatosis (19).…”

Section: Discussionmentioning

confidence: 99%

“…OTULIN is an evolutionarily highly conserved protein, and in mice complete deficiency is embryonically lethal (8). Recently, we reported patients with heterozygous germline mutations in TNFAIP3/ A20 (10), which has DUB activity for K63-linked polyubiquitin chains. Both OTULIN and A20 are important gatekeepers of innate immunity (7,11).…”

mentioning

confidence: 99%

Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease

Zhou

Demirkaya

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by loss-of-function mutations in OTULIN (FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients' fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies.OTULIN | linear deubiquitinase | NF-κB pathway | autoinflammatory disease | cytokines

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“…Increased inflammation driven by constitutively active NF-κB in patients does not seem to result in a significant increase in IL-1 or IL-18 unless their cells are treated with LPS [116] . NLRP3 expression appears to be increased and therefore primed, as…”

Section: Monogenic Autoinflammatory Diseasementioning

confidence: 99%

“…(HA20, haploinsufficiency of A20) [116] . Increased inflammation driven by constitutively active NF-κB in patients does not seem to result in a significant increase in IL-1 or IL-18 unless their cells are treated with LPS [116] .…”

Section: Monogenic Autoinflammatory Diseasementioning

confidence: 99%

Inflammasome Priming in Sterile Inflammatory Disease

Patel

Carroll

Galván-Peña

et al. 2017

Trends in Molecular Medicine

205

167

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Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease

Cited by 520 publications

References 48 publications

Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease

Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease

Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease

Inflammasome Priming in Sterile Inflammatory Disease

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