A Stk4-Foxp3–NF-κB p65 transcriptional complex promotes T
            <sub>reg</sub>
            cell activation and homeostasis

Cui, Ye; Benamar, Mehdi; Schmitz-Abe, Klaus; Krishnan, Varsha Poondi; Chen, Qian; Jugder, Bat-Erdene; Fatou, Benoit; Fong, Jason; Zhong, Yuelin; Mehta, Stuti; Buyanbat, Altantsetseg; Eklioğlu, Beray Selver; Karabiber, Esra; Barış, Safa; Kıykım, Ayça; Keleş, Sevgi; Stephen-Victor, Emmanuel; Angelini, Claudia; Charbonnier, Louis-Marie; Chatila, Talal A.

doi:10.1126/sciimmunol.abl8357

Cited by 11 publications

(10 citation statements)

References 65 publications

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“…As previous studies described, the increasing level of TNFA-NFκB could enhance the suppressive function of Treg cells through inducing the proliferation of Treg cells, resulting in the immune escape of tumor cells. [ 22 , 23 ] In addition, IL2-STAT5 could also regulate the activation of Treg cells through inducing Foxp3. [ 24 ] Besides, we found that the high risk group was also enriched in angiogenesis, TNFA-NFκB signal pathway and IL2-STAT5 signal pathway.…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of a prognostic anoikis-related gene signature in papillary thyroid carcinoma by integrated analysis of single-cell and bulk RNA-sequencing

Zheng,

Zhang,

et al. 2024

Medicine

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Papillary thyroid carcinoma (PTC) prognosis may be deteriorated due to the metastases, and anoikis palys an essential role in the tumor metastasis. However, the potential effect of anoikis-related genes on the prognosis of PTC was unclear. The mRNA and clinical information were obtained from the cancer genome atlas database. Hub genes were identified and risk model was constructed using Cox regression analysis. Kaplan–Meier (K–M) curve was applied for the survival analysis. Immune infiltration and immune therapy response were calculated using CIBERSORT and TIDE. The identification of cell types and cell interaction was performed by Seurat, SingleR and CellChat packages. GO, KEGG, and GSVA were applied for the enrichment analysis. Protein-protein interaction network was constructed in STRING and Cytoscape. Drug sensitivity was assessed in GSCA. Based on bulk RNA data, we identified 4 anoikis-related risk signatures, which were oncogenes, and constructed a risk model. The enrichment analysis found high risk group was enriched in some immune-related pathways. High risk group had higher infiltration of Tregs, higher TIDE score and lower levels of monocytes and CD8 T cells. Based on scRNA data, we found that 4 hub genes were mainly expressed in monocytes and macrophages, and they interacted with T cells. Hub genes were significantly related to immune escape-related genes. Drug sensitivity analysis suggested that cyclin dependent kinase inhibitor 2A may be a better chemotherapy target. We constructed a risk model which could effectively and steadily predict the prognosis of PTC. We inferred that the immune escape may be involved in the development of PTC.

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Section: Discussionmentioning

confidence: 99%

Identification and validation of a prognostic anoikis-related gene signature in papillary thyroid carcinoma by integrated analysis of single-cell and bulk RNA-sequencing

Zheng,

Zhang,

et al. 2024

Medicine

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“…STK4 translocate to nucleus and constitute a complex with NF-κB p65-Foxp3 that regulates Foxp3-and p65-dependent transcriptional programs. 27 Thus, STK4 positively regulate Treg differentiation or functions. Further, Treg cells suppress Th1 responses.…”

Section: Discussionmentioning

confidence: 99%

Distinguishing Clinical and Immunological Features of Combined Immune Deficiency due to Serine/Threonine Kinase 4 deficiency

Kapaklı¹,

HAZAR²,

Celik³

et al. 2023

Preprint

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Background: Serine/threonine kinase 4 (STK4) deficiency is a combined immunodeficiency with overlapping features with the autosomal dominant (AD)– and recessive (AR) forms of the Hyper IgE syndrome (HIES), including recurrent infections, eczema, eosinophilia and elevated serum IgE levels. The precise distinguishing features of STK4 deficiency versus the different forms of HIES remain unclear. Objective: We examined the comparative clinical and immunological features of STK4 deficiency versus AD- and AR forms of HIES, including signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8) respectively, with a focus on those attributes that distinguish STK4 deficiency from those disorders. Methods: Six STK4, 4 STAT3 and 14 DOCK8 deficient patients and 16 healthy controls enrolled in this study. Clinical and immunological features of the patients including detailed analysis of naïve and memory T and B cell subsets including T helper (TH), T follicular helper (TFH) and T regulatory (Treg) cells were evaluated and compared with age matched control subjects. Results: Recurrent infections and eczema were the most frequent clinical findings in AR- and eczema in AD-HIES. All STK4 deficient patients had recurrent herpetic facial lesions. Serum IgM level was significantly low in DOCK8 deficient patients compared to STAT3 and STK4 deficiency. Both CD4+T cell numbers and ratio were significantly lower in STK4 and DOCK8 deficient patients compared to control subjects. On the other hand, recent thymic emigrant (RTE) cell ratio was significantly lower, and T helper type 1 (TH1) cell frequencies were significantly higher in STK4 deficiency. While regulatory T (Treg) cell frequencies were significantly lower in DOCK8 deficiency, T helper type 17 (TH17) cell frequencies were significantly lower in both STAT3 and DOCK8 deficient patients. Conclusion: While STK4 deficiency presents with overlapping clinical and immunological features with DOCK8 deficiency, including recurrent herpetic lesion and CD4+ T cell lymphopenia, it is distinguished by the absence of severe allergic diseases and by a number of immunological findings including decreased RTE and increased TH1 cell frequencies. STK4 deficiency should be considered in patients with AR-HIES with a clinical phenotype of DOCK8 deficiency but with otherwise normal DOCK8 protein expression.

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“…Deletion of Stk4 in mouse Treg cells inhibits p65 expression, p65-Foxp3 complex formation, and Treg cell activation, ultimately leading to autoimmune lymphoproliferative disorders. 190 The IKK complex protects mature T cells from TNF-induced cell death and is important for their normal homeostasis and function. 7 The integrity of cellular function requires rapid activation and termination of NF-κB signaling, and this tight regulation is essential for normal cellular and organismal homeostasis.…”

Section: Physiology and Pathology Of Nf-κb Signalingmentioning

confidence: 99%

NF-κB in biology and targeted therapy: new insights and translational implications

Guo,

Jin,

Chen

et al. 2024

Sig Transduct Target Ther

106

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NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-κB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-κB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-κB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-κB signaling. We hope to present a stereoscopic, comprehensive NF-κB signaling that will inform future research and clinical practice.

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A Stk4-Foxp3–NF-κB p65 transcriptional complex promotes T _reg cell activation and homeostasis

Cited by 11 publications

References 65 publications

Identification and validation of a prognostic anoikis-related gene signature in papillary thyroid carcinoma by integrated analysis of single-cell and bulk RNA-sequencing

Identification and validation of a prognostic anoikis-related gene signature in papillary thyroid carcinoma by integrated analysis of single-cell and bulk RNA-sequencing

Distinguishing Clinical and Immunological Features of Combined Immune Deficiency due to Serine/Threonine Kinase 4 deficiency

NF-κB in biology and targeted therapy: new insights and translational implications

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A Stk4-Foxp3–NF-κB p65 transcriptional complex promotes T reg cell activation and homeostasis

Cited by 11 publications

References 65 publications

Identification and validation of a prognostic anoikis-related gene signature in papillary thyroid carcinoma by integrated analysis of single-cell and bulk RNA-sequencing

Identification and validation of a prognostic anoikis-related gene signature in papillary thyroid carcinoma by integrated analysis of single-cell and bulk RNA-sequencing

Distinguishing Clinical and Immunological Features of Combined Immune Deficiency due to Serine/Threonine Kinase 4 deficiency

NF-κB in biology and targeted therapy: new insights and translational implications

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Product

Resources

About

A Stk4-Foxp3–NF-κB p65 transcriptional complex promotes T _reg cell activation and homeostasis