Downregulation of anti-inflammatory A20 promotes immune escape of lung adenocarcinomas
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE148194 | GEO | 2021/04/01
REPOSITORIES: GEO
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Project description:Downregulation of anti-inflammatory A20 promotes immune escape of lung adenocarcinomas
| PRJNA623415 | ENA
Project description:Although recent progressions have provided significant mechanistic insights into the pathogenesis of pulmonary fibrosis (PF), few of anti-PF therapeutics show certain promise for this devastating disease. Chronic or repeated lung injury results in chronic inflammation, which functions as a major driven force to promote PF development. Here we report that chronic lung injury inactivates ubiquitin-modifying enzyme A20 to cause a progressive accumulation of transcription factor C/EBPb in macrophages, which produce a number of pro-fibrotic factors to promote PF development. Elevated GSK-3b expression, in response to chronic lung injury, interacts with and phosphorylates A20 to suppress C/EBPb degradation in macrophages. Enforced expression of A20 or pharmacological acceleration of C/EBPb degradation by a peptide restores the A20 activity and provides potent therapeutic efficacy against experimental PF. Our studies reveal a regulatory mechanism of the GSK-3b-A20-C/EBPb axis in alveolar macrophages, by targeting which can treat PF and fibroproliferative lung diseases.
2018-10-01 | GSE117690 | GEO
Project description:In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding A20 are also associated with systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to fibrosis in SSc, and which cell types drive disease due to SSc-specific genetic alterations. We characterized the expression and function of A20, and its negative transcriptional regulator DREAM, in patient with SSc. We found that levels of A20 were significantly reduced in SSc skin and lung biopsies, while DREAM was elevated and showed anti-correlation with A20. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulated major pathological and genomic features of SSc, whereas DREAM-null mice showed elevated A20 expression and were protected from fibrosis. In fibroblasts, A20 mitigated ex vivo profibrotic responses. An anti-fibrotic small molecule targeting the adiponectin receptors stimulated A20 expression in vitro in wildtype but not A20-deficient fibroblasts, and in bleomycin-treated mice. Thus, A20 has a novel function in negative regulation of fibroblast responses, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc, suggesting that A20 and DREAM represent novel druggable targets.
2022-02-01 | GSE194380 | GEO
Project description:Although recent progressions have provided significant mechanistic insights into the pathogenesis of pulmonary fibrosis (PF), few of anti-PF therapeutics show certain promise for this devastating disease. Chronic or repeated lung injury results in chronic inflammation, which functions as a major driven force to promote PF development. Here we report that chronic lung injury inactivates ubiquitin-modifying enzyme A20 to cause a progressive accumulation of transcription factor C/EBPb in macrophages, which produce a number of pro-fibrotic factors to promote PF development. Elevated GSK-3b expression, in response to chronic lung injury, interacts with and phosphorylates A20 to suppress C/EBPb degradation in macrophages. Enforced expression of A20 or pharmacological acceleration of C/EBPb degradation by a peptide restores the A20 activity and provides potent therapeutic efficacy against experimental PF. Our studies reveal a regulatory mechanism of the GSK-3b-A20-C/EBPb axis in alveolar macrophages, by targeting which can treat PF and fibroproliferative lung diseases.
2018-10-01 | GSE117649 | GEO
Project description:Inflammation is a well-known driver of lung tumorigenesis. One strategy by which tumor cells escape tight homeostatic control is by decreasing the expression of the potent anti-inflammatory protein tumor necrosis factor alpha-induced protein 3 (TNFAIP3), also known as A20. We observed that tumor cell intrinsic loss of A20 markedly enhanced lung tumorigenesis and was associated with reduced CD8+ T cell-mediated immune surveillance in patients with lung cancer and in mouse models. In mice, we observed that this effect was completely dependent on increased cellular sensitivity to interferon-γ (IFN-γ) signaling by aberrant activation of TANK-binding kinase 1 (TBK1) and increased downstream expression and activation of signal transducer and activator of transcription 1 (STAT1). Interrupting this autocrine feed forward loop by knocking out IFN-α/β receptor completely restored infiltration of cytotoxic T cells and rescued loss of A20 depending tumorigenesis. Downstream of STAT1, programmed death ligand 1 (PD-L1) was highly expressed in A20 knockout lung tumors. Accordingly, immune checkpoint blockade (ICB) treatment was highly efficient in mice harboring A20-deficient lung tumors. Furthermore, an A20 loss-of-function gene expression signature positively correlated with survival of melanoma patients treated with anti-programmed cell death protein 1. Together, we have identified A20 as a master immune checkpoint regulating the TBK1-STAT1-PD-L1 axis that may be exploited to improve ICB therapy in patients with lung adenocarcinoma.
| S-EPMC7611502 | biostudies-literature
Project description:The NLRP3 inflammasome, a pivotal component of innate immunity, has been implicated in various inflammatory disorders. The ubiquitin-editing enzyme A20 is well known to regulate inflammation and maintain homeostasis. However, the precise molecular mechanisms by which A20 modulates the NLRP3 inflammasome remain poorly understood. Here our study revealed that macrophages deficient in A20 exhibit increased protein abundance and elevated mRNA level of NIMA-related kinase 7 (NEK7). Importantly, A20 directly binds with NEK7, mediating its K48-linked ubiquitination, thereby targeting NEK7 for proteasomal degradation. Our results demonstrate that A20 enhance the ubiquitination of NEK7 at K189 and K293 ubiquitinated sites, with K189 playing a crucial role in the binding of NEK7 to A20, albeit not significantly influencing the interaction between NEK7 and NLRP3. Furthermore, A20 disrupts the association of NEK7 with the NLRP3 complex, potentially through the OTU domain and/or synergistic effect of ZnF4 and ZnF7 motifs. Significantly, NEK7 deletion markedly attenuates the activation of the NLRP3 inflammasome in A20-deficient conditions, both in vitro and in vivo. This study uncovers a new mechanism by which A20 inhibits the NLRP3 inflammasome.
2024-07-03 | GSE253265 | GEO
Project description:The goal of this study is to elucidate the role of microglial A20 in maintaining brain homeostasis, comparing fully deficient to partially deficient microglia tissue
2020-09-27 | GSE123033 | GEO
Project description:A20 is a negative regulator of NF-κB signaling, crucial to control inflammatory responses and ensure tissue homeostasis. A20 is thought to restrict NF-κB activation both by its ubiquitin-editing activity as by non-enzymatic activities. Besides its role in NF-κB signaling, A20 also acts as a protective factor inhibiting apoptosis and necroptosis. Because of the ability of A20 to both ubiquitinate and deubiquitinate substrates and its involvement in many cellular processes, we hypothesized that deletion of A20 might generally impact on protein levels, thereby disrupting cellular processes. We performed a differential proteomics study of bone marrow derived macrophages (BMDMs) from control and myeloid-specific A20 knockout mice, both in untreated conditions and after LPS and TNF treatment, and demonstrate proteome-wide changes in protein expression upon A20 deletion. Several inflammatory proteins are up-regulated in the absence of A20, even without an inflammatory stimulus. Depending on the treatment and the time, more proteins are regulated. Together these changes may affect multiple signaling pathways disturbing tissue homeostasis and inducing (autoimmune) inflammation, as suggested by genetic studies in patients.
2018-05-15 | PXD008726 | Pride
Project description:Unique and shared cytogenetic abnormalities have been documented for marginal zone lymphomas (MZLs) arising at different sites. Recently, homozygous deletions of the chromosomal band 6q23, involving the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) gene, a negative regulator of NF-kappa B, were described in ocular adnexal MZL, suggesting a role for A20 as a tumor suppressor in this disease entity. Here, we investigated inactivation of A20 by DNA mutations or deletions in a panel of extranodal (EMZL), nodal (NMZL) and splenic (SMZL) MZLs. Inactivating mutations encoding truncated A20 proteins were identified in 6/32 (18.8%) MZLs, including 3/11 (27.3%) EMZLs, 2/9 (22.2%) NMZLs, and 1/12 (8.3%) SMZLs. Two additional unmutated non-splenic MZLs also showed mono- or biallelic A20 deletions by FISH and/or array-CGH. Thus, A20 loss by both somatic mutations and/or deletions represents a common genetic aberration across all MZL subtypes, which may contribute to lymphomagenesis by inducing constitutive NF-kappa B activation. Keywords: Genome variation profiling by SNP array 27 MZL samples. No technical replications.
2009-04-01 | E-GEOD-13989 | biostudies-arrayexpress
Project description:Objectives: Genetic variations in TNFAIP3 (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis. Methods: CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A knock-in cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was adressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926. Results: Genetic disruption of A20 DUB domain in human and murine myeoloid cells did not give rise to enhanced NF-κB signaling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes. Conclusions: We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.
2019-07-10 | GSE116780 | GEO