Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation

Wertz, Ingrid E.; Newton, Kim; Seshasayee, Dhaya; Kusam, Saritha; Lam, Cynthia; Zhang, Juan; Popovych, Nataliya; Helgason, Elizabeth; Schoeffler, Allyn J.; Jeet, Surinder; Ramamoorthi, Nandhini; Kategaya, Lorna; Newman, Robert J.; Horikawa, Keisuke; Dugger, Debra L.; Sandoval, Wendy; Mukund, Susmith; Zindal, Anuradha; Martin, Flavius; Quan, Clifford; Tom, Jeffrey; Fairbrother, Wayne J.; Townsend, Michael J.; Warming, Søren; DeVoss, Jason; Liu, Jinfeng; Dueber, Erin C.; Caplazi, Patrick; Lee, Wyne P.; Goodnow, Christopher C.; Balázs, Mercedesz; Yu, Kebing; Kolumam, Ganesh; Dixit, Vishva M.

doi:10.1038/nature16165

Cited by 230 publications

(255 citation statements)

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“…S5C). RIPK1 and TNFR1 require the assembly of K63 and linear polyubiquitin chains for proper signaling activity, and they are subject to deubiquitination by A20 and OTULIN (14). The K63 ubiquitination of RIPK1 was not affected by the presence of mutant OTULIN proteins (Fig.…”

Section: Significancementioning

confidence: 91%

“…S4 B and C). OTULIN cleaves Met1-linked linear polyubiquitin chains from target substrates, such as NEMO (IKKγ), RIPK1, ASC, and TNFR1 to restrict signaling activation and propagation (7,14,15). To investigate the effect of OTULIN mutations on its deubiquitinase function, we cotransfected WT and mutant OTULIN plasmids into HEK293 cells along with plasmids encoding the LUBAC subunits, mono specific-ubiquitin plasmid, and each of the OTULIN substrates NEMO (Fig.…”

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

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.

229

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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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Section: Significancementioning

confidence: 91%

Section: Significancementioning

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.

229

275

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“…TNFAIP3, an immediate early response gene, serves a critical role in the negative regulation of the NF-κB signaling pathway, as well as in β cell protection, through its actions as a dual ubiquitin-editing protein (49,57). The mechanism through which TNFAIP3 turns off inflammation signaling has previously been described as the disruption of ubiquitin enzyme complexes (58); in cells expressing deficient or mutant TNFAIP3 protein, there is defective removal of Lys63-linked ubiquitin from ubiquitin enzyme complexes following stimulation with TNF (59). Our previous study found that the plasma levels of TNF-α and IL-1β were significantly increased, and TNFAIP3 mRNA and protein expression levels were significant decreased in the peripheral blood mononuclear cells of diabetes patients (60).…”

Section: A B Cmentioning

confidence: 99%

Tumor necrosis factor α-induced protein-3 protects zinc transporter 8 against proinflammatory cytokine-induced downregulation

Cheng¹,

Zhang²,

Chen³

2016

Experimental and Therapeutic Medicine

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Abstract. Zinc transporter 8 (ZnT8) is exclusively expressed in the pancreatic islet and is essential for insulin crystallization, hexamerization and secretion. Tumor necrosis factor α-induced protein-3 (TNFAIP3) is a zinc finger protein that serves a major role in the negative feedback regulation of NF-κB signaling in response to multiple stimuli, and is a central regulator of immunopathology. Although the role of TNFAIP3 in diabetes has been extensively studied, its effect on ZnT8 has not been fully elucidated. The present study aimed to verify whether proinflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β), are able to affect ZnT8 expression in islet cells. In addition, the study aimed to determine the effect of TNFAIP3 overexpression on cytokine-altered ZnT8 activity, considering its effect on NF-κB signaling. Cell-based studies using NIT-1 cells overexpressing TNFAIP3 were used to assess the effect of cytokines on ZnT8 and NF-κB activation, as well as the effect of TNFAIP3 on ZnT8 expression. Western blot analysis and immunofluorescence staining were employed to determine the protein expression and NF-κB activation, respectively. The results indicated that cytokine stimulation led to TNFAIP3 upregulation, ZnT8 downregulation and NF-κB activation. Furthermore, TNFAIP3 overexpression protected ZnT8 from cytokine-induced downregulation. In conclusion, the current results suggest that inflammation or TNFAIP3 dysfunction may be involved in the pathogenesis of diabetes via ZnT8 expression, besides from islet cell apoptosis. In addition, restricting inflammation and enhancing TNFAIP3 expression may exert a positive effect in diabetes prevention, treatment and pancreatic cell transplantation. IntroductionDiabetes, a class of metabolic diseases that are prevalent worldwide affecting 422 million people in 2014 according to the World Health Organization (1), is characterized by hyperglycemia and can cause severe damage to different organs, particularly the eyes, kidneys, nerves, heart and blood vessels. According to the American Diabetes Association, the disease can be classified into two main types, including type 1 and type 2 diabetes (2). Type 1 diabetes results from a cell-mediated autoimmune attack on β cells, whereas type 2 diabetes is a low-grade, chronic inflammatory disease that shares a common final pathway with type 1 diabetes, in which activation of the nuclear factor κB (NF-κB) signaling pathway causes a reduction in pancreatic β cells (3-10).Zinc participates in numerous biological processes, and is essential for the correct processing, storage, secretion, and function of insulin in pancreatic β cells (11-13). Zinc flux is controlled by two types of transporters: The zinc transporter (ZnT; also known as SLC30A) family, and the Zrt-and Irt-like protein (ZIP) family. Typically, the ZnT family regulates Zn 2+ efflux out of the cytoplasm, while the ZIP family regulates Zn 2+ influx into the cytoplasm. Although 10 ZnTs and 14 ZIPs have been identified in mammals, ZnT8 is exclusiv...

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“…2 and 3 Fig. 3; Wertz et al, 2015). However, four cysteines (i.e., C X4 C X11 C X2 C and C X2 C X11 C X2 C) in seven regions similar to the human Zf domains were well-conserved in fish.…”

Section: Structural Analysis Of Fugu A20 Genementioning

confidence: 98%

Molecular Characterization and Expression Analysis of Tumor Necrosis Factor Alpha-induced Protein 3 (TNFAIP3/A20) Gene from Japanese Pufferfish <i>Takifugu rubripes</i>

et al. 2017

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Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation

Cited by 230 publications

References 50 publications

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

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

Tumor necrosis factor α-induced protein-3 protects zinc transporter 8 against proinflammatory cytokine-induced downregulation

Molecular Characterization and Expression Analysis of Tumor Necrosis Factor Alpha-induced Protein 3 (TNFAIP3/A20) Gene from Japanese Pufferfish <i>Takifugu rubripes</i>

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