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A20, encoded by TNFAIP3, is a critical negative regulator of immune activation. A20 is a ubiquitin editing enzyme with multiple domains, each of which mediates or stabilizes a key ubiquitin modification. A20 targets diverse proteins that are involved in pleiotropic immunologic pathways. The complexity of A20-mediated immunomodulation is illustrated by the varied effects of A20 deletion in different cell types and disease models. Clinically, the importance of A20 is highlighted by its extensive associations with human disease. A20 germline variants are associated with a wide range of inflammatory diseases, while somatic mutations promote development of B cell lymphomas. More recently, the discovery of A20 haploinsufficiency (HA20) has provided real world evidence for the role of A20 in immune cell function. Originally described as an autosomal dominant form of Behcet’s disease, HA20 is now considered a complex inborn error of immunity with a broad spectrum of immunologic and clinical phenotypes.

Autoinflammatory diseases are caused by defects in genes that regulate the innate immunity. Recently, the scope of autoinflammation has been broadened to include diseases that result from dysregulations in protein modifications by the highly conserved ubiquitin (Ub) peptides. Thus far these diseases consist of linear ubiquitin chain assembly complex (LUBAC) and OTULIN deficiencies, and haploinsufficiency of A20. The LUBAC is critical for linear ubiquitination of key signaling molecules in immune response pathways, while deubiquitinase enzymes, OTULIN and TNFAIP3/A20, reverse the effects of ubiquitination by hydrolyzing linear (Met1) and Lys63 (K63) Ub moieties, respectively, from conjugated proteins. Consequently, OTULIN or A20-deficient cells have an excess of Met1 or K63 Ub chains on NEMO, RIPK1, and other target substrates, which lead to constitutive activation of the NF-kB pathway. Mutant cells produce elevated levels of many proinflammatory cytokines and respond to therapy with cytokine inhibitors. Patients with an impairment in LUBAC stability have compromised NF-kB responses in non-immune cells such as fibroblasts, while their monocytes are hyperresponsive to IL-1β. Discoveries of germline mutations in enzymes that regulate protein modifications by Ub define a new category of autoinflammatory diseases caused by upregulations in the NF-kB signaling. The primary aim of this review is to summarize the latest developments in our understanding of the etiology of autoinflammation.

Linear polyubiquitination of proteins has recently been implicated in NF‐κB signalling and is mediated by the linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL‐1, HOIP and Sharpin. However, the mechanisms that regulate linear ubiquitination are still unknown. Here, we show that A20 is rapidly recruited to NEMO and LUBAC upon TNF stimulation and that A20 inhibits LUBAC‐induced NF‐κB activation via its C‐terminal zinc‐finger 7 (ZF7) domain. Expression of a polypeptide corresponding to only ZF7 was sufficient to inhibit TNF‐induced NF‐κB activation. Both A20 and ZF7 can form a complex with NEMO and LUBAC, and are able to prevent the TNF‐induced binding of NEMO to LUBAC. Finally, we show that ZF7 preferentially binds linear polyubiquitin chains in vitro , indicating A20–ZF7 as a novel linear ubiquitin‐binding domain (LUBID). We thus propose a model in which A20 inhibits TNF‐ and LUBAC‐induced NF‐κB signalling by binding to linear polyubiquitin chains via its seventh zinc finger, which prevents the TNF‐induced interaction between LUBAC and NEMO. The ubiquitin‐editing enzyme A20, known to affect NF‐κB activation via both catalytic and structural functions, possesses a linear ubiquitin chain binding domain that interferes with the essential NEMO–LUBAC interactions.

Periodontitis is a prevalent chronic disease that results in loss of periodontal ligament and bone resorption. Triggered by pathogens and prolonged inflammation, periodontitis is modulated by the immune system, especially pro-inflammatory cells, such as T helper (Th) 17 cells. Originated from CD4 + Th cells, Th17 cells play a central role for they drive and regulate periodontal inflammation. Cytokines secreted by Th17 cells are also major players in the pathogenesis of periodontitis. Given the importance of Th17 cells, modulators of Th17 cells are of great clinical potential and worth of discussion. This review aims to provide an overview of the current understanding of the effect of Th17 cells on periodontitis, as well as a brief discussion of current and potential therapies targeting Th17 cells. Lastly, we highlight this article by summarizing the causal relationship between A20 (encoded by TNFAIP3 ), an anti-inflammatory molecule, and Th17 cell differentiation.

Breast cancer stem cells (BCSCs) are a tiny population of self-renewing cells that may contribute to cancer initiation, progression, and resistance to therapy in patients. In our prior study, we found that tumor necrosis factor alpha-induced protein 3 (TNFAIP3) is necessary for fibroblast growth factors receptor 1 (FGFR1) signaling-promoted tumor growth and progression in breast cancer (BC). This study aims to investigate the involvement of TNFAIP3 in regulating BCSCs. In this work, we showed that ALDH-positive BCSCs were increased by activating the FGFR1-MEK-ERK pathway, meanwhile utilizing FGFR1 inhibitor, MEK inhibitor, or ERK inhibitor reversed the phenomenon in BC cells. Moreover, ALDH-positive BCSCs were decreased in TNFAIP3-knockout or TNFAIP3-depressing cells. In vivo analysis displayed that TNFAIP3-silenced MDA-MB-231 xenografts developed smaller tumors and ALDH immunostaining levels were significantly lower in TNFAIP3-depressing or TNFAIP3-knockout tumor tissues. Besides, our results also revealed that TNFAIP3 influences the transcription stemness factors gene expression. Taken together, TNFAIP3 could be a potential regulator in FGFR1-MEK-ERK-promoted ALDH-positive BCSCs.

Background Haploinsufficiency of A20 (HA20) is caused by loss-of-function TNFAIP3 variants. Phenotypic and genetic features of HA20 remain uncertain; therefore, the clinical distinction between HA20 and Behçet’s disease (BD) requires clarification. Methods We have collected 12 Japanese BD-like families. Probands of these families were analyzed by whole exome sequencing (WES) and subsequent Sanger sequencing. Clinical features were compared between 54 HA20 patients (including previously reported and new cases) and 520 Japanese BD patients. Results We identified c.1434C>A:p.(Cys478*) in one family and a 236 kb deletion at 6q23.3 containing TNFAIP3 in another family. Four HA20 patients in the two families presented with childhood-onset recurrent oral and genital ulcers and were initially diagnosed and treated as BD. Consistent with the clinical features of HA20, recurrent, refractory fever attacks (three of four patients), and digestive ulcers (two of the four patients) were observed. A comparison of clinical features between HA20 patients and cohorts of BD patients revealed several critical features specific to HA20. These were early-onset, familial occurrence, recurrent fever attacks, gastrointestinal involvement, and infrequent ocular involvement. Conclusions We identified a novel nonsense variant and deletion of the entire TNFAIP3 gene in two unrelated Japanese HA20 families. Genetic screening of TNFAIP3 should be considered for familial BD-like patients with early-onset recurrent fevers.

Background To investigate the role of PCBP1-AS1 in pancreatic cancer (PCa) liver metastasis and its underlying mechanisms. Methods We analyzed the expression patterns of PCBP1-AS1, miR-125b-5p, and TNFAIP3 in PCa tissues, normal tissues, and peripheral blood exosomes. The relationships between these molecules and PCa pathological features, including liver metastasis, were examined. Dual-luciferase reporter assays confirmed the targeting interactions among PCBP1-AS1, miR-125b-5p, and TNFAIP3. We constructed PCa cell lines overexpressing miR-125b-5p and/or TNFAIP3, as well as PCBP1-AS1 and/or miR-125b-5p, to assess their effects on TNFAIP3 expression and cellular behaviors. The impact of exosomes from transfected or untransfected PCa cells on TNFAIP3 levels, NF-κB activation, and hepatic stellate cells (HSCs) to cancer-associated fibroblasts (CAFs) transformation was evaluated. A PCa liver metastasis model was constructed to study the effects of exosomes on HSCs activation. Results MiR-125b-5p was largely upregulated in PCa tissues and peripheral blood exosomes, with high expression correlating with advanced disease stage and liver metastasis. MiR-125b-5p promoted PCa progression by targeting TNFAIP3. Overexpression of miR-125b-5p further enhanced TNFAIP3 suppression, p-p65 activation, and HSCs-to-CAFs transformation induced by PCa-derived exosomes, while miR-125b-5p inhibition reversed these effects. Preconditioning with PCa-derived exosomes facilitated liver metastasis in vivo, with increased miR-125b-5p levels exacerbating metastasis by targeting TNFAIP3 and activating NF-κB. Reduced PCBP1-AS1 expression was associated with poorer survival in PCa patients and was significantly lower in tissues from patients with liver metastases. PCBP1-AS1 counteracted miR-125b-5p-mediated TNFAIP3 suppression and mitigated the tumor-promoting effects of miR-125b-5p. Conclusions PCBP1-AS1 enhances TNFAIP3 expression by targeting miR-125b-5p, thereby inhibiting PCa progression. Reduced PCBP1-AS1 in PCa increases miR-125b-5p levels in exosomes, activating NF-κB and promoting HSCs-to-CAFs transformation, creating a favorable microenvironment for liver metastasis.

The ubiquitin-editing enzyme A20 is known to inhibit the NF-κB transcription factor in the Toll-like receptor (TLR) pathways, thereby negatively regulating inflammation. However, its role in the TLR signaling pathway in fish is still largely unknown. Here, we identified a gene encoding A20 (OmA20) in rainbow trout, Oncorhynchus mykiss, and investigated its role in TLR response regulation. The deduced amino acid sequence of OmA20 contained a conserved N-terminal ovarian tumor (OTU) domain and seven C-terminal zinc-finger (ZnF) domains. Lipopolysaccharide (LPS) stimulation increased OmA20 expression in RTH-149 cells. In LPS-stimulated RTH-149 cells, gain- and loss-of-function experiments revealed that OmA20 inhibited MAPK and NF-κB activation, as well as the expression of pro-inflammatory cytokines. OmA20 interacted with TRAF6, a key molecule involved in the activation of TLR-mediated NF-κB signaling pathways. LPS treatment increased the K63-linked polyubiquitination of TRAF6 in RTH-149 cells, which was suppressed when OmA20 was forced expression. Furthermore, mutations in the OTU domain significantly decreased deubiquitination of the K63-linked ubiquitin chain on TRAF6, indicating that deubiquitinase activity is dependent on the OTU domain. These findings suggest that OmA20, like those of mammals, reduces LPS-induced inflammation in rainbow trout, most likely by regulating K63-linked ubiquitination of TRAF6.

Aims/hypothesis NF-κB activation unites metabolic and inflammatory responses in many diseases yet less is known about the role that NF-κB plays in normal metabolism. In this study we investigated how RELA  impacts the beta cell transcriptional landscape and provides network control over glucoregulation. Methods We generated novel mouse lines harbouring beta cell-specific deletion of either the Rela gene, encoding the canonical NF-κB transcription factor p65 (βp65KO mice), or the Ikbkg gene, encoding the NF-κB essential modulator NEMO (βNEMOKO mice), as well as βA20Tg mice that carry beta cell-specific and forced transgenic expression of the NF-κB-negative regulator gene Tnfaip3 , which encodes the A20 protein. Mouse studies were complemented by bioinformatics analysis of human islet chromatin accessibility (assay for transposase-accessible chromatin with sequencing [ATAC-seq]), promoter capture Hi-C (pcHi-C) and p65 binding (chromatin immunoprecipitation–sequencing [ChIP-seq]) data to investigate genome-wide control of the human beta cell metabolic programme. Results Rela deficiency resulted in complete loss of stimulus-dependent inflammatory gene upregulation, consistent with its known role in governing inflammation. However, Rela deletion also rendered mice glucose intolerant because of functional loss of insulin secretion. Glucose intolerance was intrinsic to beta cells as βp65KO islets failed to secrete insulin ex vivo in response to a glucose challenge and were unable to restore metabolic control when transplanted into secondary chemical-induced hyperglycaemic recipients. Maintenance of glucose tolerance required Rela but was independent of classical NF-κB inflammatory cascades, as blocking NF-κB signalling in vivo by beta cell knockout of Ikbkg (NEMO), or beta cell overexpression of Tnfaip3 (A20), did not cause severe glucose intolerance. Thus, basal p65 activity has an essential and islet-intrinsic role in maintaining normal glucose homeostasis. Genome-wide bioinformatic mapping revealed the presence of p65 binding sites in the promoter regions of specific metabolic genes and in the majority of islet enhancer hubs (~70% of ~1300 hubs), which are responsible for shaping beta cell type-specific gene expression programmes. Indeed, the islet-specific metabolic genes Slc2a2 , Capn9 and Pfkm identified within the large network of islet enhancer hub genes showed dysregulated expression in βp65KO islets. Conclusions/interpretation These data demonstrate an unappreciated role for RELA as a regulator of islet-specific transcriptional programmes necessary for the maintenance of healthy glucose metabolism. These findings have clinical implications for the use of anti-inflammatories, which influence NF-κB activation and are associated with diabetes. Graphical Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive form of non-Hodgkin's lymphoma. Extracellular vesicles (EVs) derived from cancer cells are known to modify the tumor microenvironment. The aim of the present study was to investigate the role of miR-125b-3p carried by EVs in DLBCL in vitro and in vivo. TNFAIP3 expression in patient lesions was measured and the upstream miR that regulates TNFAIP3 was predicted using the starBase database. EVs were isolated from DLBCL cells and identified. DLBCL cells were transfected with pcDNA to overexpress TNFAIP3 or inhibit miR-125b-5p expression, incubated with EVs, and treated with rituximab to compare cell growth and TNFAIP3/CD20 expression. DLBCL model mice were administered EVs, conditioned medium, and rituximab to observe changes in tumor size, volume, and weight. TNFAIP3 was downregulated in patients with DLBCL and its levels further decreased in patients with drug-resistant DLBCL. Overexpression of TNFAIP3 in DLBCL cells enhanced the inhibitory effect of rituximab and increased CD20 expression. miR-125b-5p targeted TNFAIP3. Inhibition of miR-125b-5p enhanced the inhibitory effect of rituximab in DLBCL cells. The EV-carried miR-125b-5p reduced the sensitivity of DLBCL cells to rituximab, which was averted by overexpression of TNFAIP3. EVs reduced the sensitivity of DLBCL model mice to rituximab via the miR-125b-5p/TNFAIP3 axis. The study findings indicate that the tumor-derived EVs carrying miR-125b-5p can enter DLBCL cells and target TNFAIP3, thus reducing the sensitivity of DLBCL to rituximab, which may provide a novel therapeutic approach for DLBCL.