ZNF341 controls STAT3 expression and thereby immunocompetence
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA421196 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6348970.fastq.gz | Fastqsanger.gz | |||
| SRR6348968.fastq.gz | Fastqsanger.gz | |||
| SRR6348969.fastq.gz | Fastqsanger.gz |
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Project description:Signal-transducer-and-activator-of-transcription-3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-IgE syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished Th17 cell numbers, in absence of STAT3 mutations. We identified homozygous nonsense mutations in ZNF341, encoding a zinc-finger transcription factor. Wildtype-ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindred. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.
2018-05-02 | GSE107719 | GEO
Project description:Signal transducer and activator of transcription 3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled, and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-immunoglobulin E (IgE) syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished T helper 17 cell numbers, in absence of STAT3 mutations. We identified two distinct homozygous nonsense mutations in ZNF341, which encodes a zinc finger transcription factor. Wild-type ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.
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Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFκB-induced IL-8-expression by sequestering NFκB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance WT: Control lung; KRAS: Lung tumors expressing KRAS G12D; KRAS STAT3 KO: Lung tumors expressing KRAS G12D- STAT3 deficient; tumors of four mice pooled per sample
2015-02-05 | E-GEOD-52798 | biostudies-arrayexpress
Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFκB-induced IL-8-expression by sequestering NFκB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance
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Project description:Germinal centers (GCs), sites of antibody affinity maturation, are organized into dark (DZ) and light (LZ) zones. Here, we uncovered a B cell intrinsic role for STAT3 in GC DZ and LZ organization. Altered zonal organization of STAT3-deficient GCs dampened GC output of long- lived plasma cells (LL-PCs) but increased memory B cells (MBCs). Tfh-GC B cell interaction drive STAT3 tyrosine 705 and serine 727 phosphorylation in LZ B cells, facilitating their recycling into the DZ. An inducible system confirmed STAT3 is not involved in initiating or maintaining the GC but sustains GC zonal organization by regulating GC B cell recycling. RNAseq and ChIPseq analysis identified genes regulated by STAT3 that are critical for LZ cell recycling and transiting through the DZ proliferation and differentiation phases of the DZ. Thus, STAT3 signaling in B cells controls GC zone organization and recycling, and GC egress of LL- PCs, but negatively regulates MBC output.
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Project description:Chronically infecting pathogens avoid clearance by the innate immune system by promoting premature transition from an initial pro-inflammatory response towards an anti-inflammatory tissue-repair response. STAT3, a central regulator of inflammation, controls this transition and thus is targeted by numerous chronic pathogens. Here we show that BepD, an effector of the chronic bacterial pathogen Bartonella henselae targeted to infected host cells, establishes an exceptional pathway for canonical STAT3 activation, thereby impairing secretion of pro-inflammatory TNF-α and stimulating secretion of anti-inflammatory IL-10. Tyrosine phosphorylation of EPIYA-related motifs in BepD facilitates STAT3 binding and activation via c-Abl-dependent phosphorylation of Y705. The tyrosine-phosphorylated scaffold of BepD thus represents a signaling hub for intrinsic STAT3 activation that is independent from canonical STAT3 activation via transmembrane receptor-associated Janus kinases. We anticipate that our findings on a molecular shortcut to STAT3 activation will inspire new treatment options for chronic infections and inflammatory diseases.
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Project description:Germinal centers (GCs), sites of antibody affinity maturation, are organized into dark (DZ) and light (LZ) zones. Here, we uncovered a B cell intrinsic role for STAT3 in GC DZ and LZ organization. Altered zonal organization of STAT3-deficient GCs dampened GC output of long-lived plasma cells (LL-PCs) but increased memory B cells (MBCs). Tfh-GC B cell interaction drive STAT3 tyrosine 705 and serine 727 phosphorylation in LZ B cells, facilitating their recycling into the DZ. An inducible system confirmed STAT3 is not involved in initiating or maintaining the GC but sustains GC zonal organization by regulating GC B cell recycling. RNAseq and ChIPseq analysis identified genes regulated by STAT3 that are critical for LZ cell recycling and transiting through the DZ proliferation and differentiation phases of the DZ. Thus, STAT3 signaling in B cells controls GC zone organization and recycling, and GC egress of LL-PCs, but negatively regulates MBC output.
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Project description:Metastatic melanoma is hallmarked by its ability to switch oncogenic MITF expression. Here we tested the impact of STAT3 on melanoma onset and progression in association with MITF expression levels. We established a mouse melanoma model for deleting Stat3 specifically in melanocytes with specific expression of human hyperactive NRASQ61K in an Ink4a deficient background. Mice with tissue specific Stat3 deletion showed an early onset of disease, but displayed significantly diminished lung metastasis. Whole genome expression profiling also revealed a reduced invasion phenotype, which was functionally confirmed in 3D melanoma model systems. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in up-regulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3 induced CEBPa/b expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that STAT3 enabled CEBPa/b binding to the MITF enhancer region thereby silencing it. We conclude that STAT3 is a metastasis driver able to antagonize the MITF oncogene via direct induction of CEBP family member transcription facilitating RAS-RAF-driven melanoma metastasis.
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Project description:Many patients have cancers that have increased activity of a protein called STAT3 that contributes critically to the development and growth of their cancer. Despite our knowledge of STAT3’s importance to cancer, scientists and doctors have not developed a drug that targets it and that patients can take to treat their cancer more effectively than treatments that are now available. Tvardi Therapeutics, Incorporated has developed a compound, TTI-101, which can be given by mouth and acts as a direct inhibitor of STAT3. Administration of TTI-101 to mice demonstrated that it blocked growth of cancers of the breast, head and neck, lung, and liver and it was safe when administered at high doses to mice, rats, and dogs. In this application, Tvardi is proposing to further develop TTI-101 for treatment of solid tumors for which the prognosis is dismal. The investigators will determine how safe it is when administered to patients with cancer, determine whether an adequate dose can be administered to patients with cancer that will block STAT3 in their cancer, and determine whether treatment with TTI-101 leads to reduced growth of their cancer.
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