scholarly journals FOXP3 and Tip60 Structural Interactions Relevant to IPEX Development Lead to Potential Therapeutics to Increase FOXP3 Dependent Suppressor T Cell Functions

2021 ◽  
Vol 9 ◽  
Author(s):  
Payal Grover ◽  
Peeyush N. Goel ◽  
Ciriaco A. Piccirillo ◽  
Mark I. Greene
Keyword(s):  
Treg Cells ◽  
Interacting Protein ◽  
Post Translational Modifications ◽  
Cell Functions ◽  
Forkhead Box ◽  
And Function ◽  
Treg Development ◽  
Essential Subunit ◽  
Potential Therapeutics

Regulatory T (Treg) cells play a role in the maintenance of immune homeostasis and are critical mediators of immune tolerance. The Forkhead box P3 (FOXP3) protein acts as a regulator for Treg development and function. Mutations in the FOXP3 gene can lead to autoimmune diseases such as Immunodysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome in humans, often resulting in death within the first 2 years of life and a scurfy like phenotype in Foxp3 mutant mice. We discuss biochemical features of the FOXP3 ensemble including its regulation at various levels (epigenetic, transcriptional, and post-translational modifications) and molecular functions. The studies also highlight the interactions of FOXP3 and Tat-interacting protein 60 (Tip60), a principal histone acetylase enzyme that acetylates FOXP3 and functions as an essential subunit of the FOXP3 repression ensemble complex. Lastly, we have emphasized the role of allosteric modifiers that help stabilize FOXP3:Tip60 interactions and discuss targeting this interaction for the therapeutic manipulation of Treg activity.

scholarly journals FOXL2: a central transcription factor of the ovary

2013 ◽  
Vol 52 (1) ◽  
pp. R17-R33 ◽  
Author(s):  
Adrien Georges ◽  
Aurelie Auguste ◽  
Laurianne Bessière ◽  
Anne Vanet ◽  
Anne-Laure Todeschini ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Forkhead Transcription Factor ◽  
Gene Encoding ◽  
Post Translational Modifications ◽  
Forkhead Box ◽  
Molecular Aspects ◽  
And Function ◽  
Craniofacial Defects ◽  
The Impact

Forkhead box L2 (FOXL2) is a gene encoding a forkhead transcription factor preferentially expressed in the ovary, the eyelids and the pituitary gland. Its germline mutations are responsible for the blepharophimosis ptosis epicanthus inversus syndrome, which includes eyelid and mild craniofacial defects associated with primary ovarian insufficiency. Recent studies have shown the involvement of FOXL2 in virtually all stages of ovarian development and function, as well as in granulosa cell (GC)-related pathologies. A central role of FOXL2 is the lifetime maintenance of GC identity through the repression of testis-specific genes. Recently, a highly recurrent somatic FOXL2 mutation leading to the p.C134W subtitution has been linked to the development of GC tumours in the adult, which account for up to 5% of ovarian malignancies. In this review, we summarise data on FOXL2 modulators, targets, partners and post-translational modifications. Despite the progresses made thus far, a better understanding of the impact of FOXL2 mutations and of the molecular aspects of its function is required to rationalise its implication in various pathophysiological processes.

scholarly journals An expanded population of pathogenic regulatory T cells in giant cell arteritis is abrogated by IL-6 blockade therapy

2016 ◽  
Vol 76 (5) ◽  
pp. 898-905 ◽  
Author(s):  
Chie Miyabe ◽  
Yoshishige Miyabe ◽  
Klemen Strle ◽  
Nancy D Kim ◽  
John H Stone ◽  
...  
Keyword(s):  
Giant Cell Arteritis ◽  
Giant Cell ◽  
Treg Cells ◽  
Therapeutic Effects ◽  
Exon 2 ◽  
Disease Remission ◽  
Randomised Controlled ◽  
And Function ◽  
Active Disease

ObjectivesRandomised-controlled trials have recently proven the efficacy of the interleukin (IL)-6 receptor antagonist tocilizumab (TCZ) in giant cell arteritis (GCA). However, the mechanism of action of IL-6 blockade in this disease is unknown. Moreover, the role of regulatory T (Treg) cells in the pathogenesis of GCA remains underexplored. Given the plasticity of Tregs and the importance of IL-6 in their biology, we hypothesised that TCZ might modulate the Treg response in GCA. We therefore characterised the Treg compartment of patients with GCA treated with TCZ.MethodsWe classified 41 patients with GCA into three groups: active disease (aGCA, n=11), disease remission on corticosteroids (rGCA-CS, n=19) and disease remission on TCZ (rGCA-TCZ, n=11). Healthy controls (HCs) were included for comparison. We determined the frequency, phenotype and function of peripheral blood Tregs.ResultsPatients with aGCA demonstrated a hypoproliferating Treg compartment enriched in IL-17-secreting Tregs (IL-17+Tregs). Tregs in patients with aGCA disproportionally expressed a hypofunctional isoform of Foxp3 that lacks exon 2 (Foxp3Δ2). Foxp3Δ2-expressing Tregs coexpressed CD161, a marker commonly associated with the Th17 linage, significantly more often than full-length Foxp3-expressing Tregs. Compared with those of HCs, GCA-derived Tregs demonstrated impaired suppressor capacity. Treatment with TCZ, in contrast to CS therapy, corrected the Treg abnormalities observed in aGCA. In addition, TCZ treatment increased the numbers of activated Tregs (CD45RA−Foxp3high) and the Treg expression of markers of trafficking (CCR4) and terminal differentiation (CTLA-4).ConclusionsTCZ may exert its therapeutic effects in GCA by increasing the proliferation and activation of Tregs, and by reverting the pathogenic Treg phenotype seen during active disease.

scholarly journals Role of Phosphodiesterase 7 (PDE7) in T Cell Activity. Effects of Selective PDE7 Inhibitors and Dual PDE4/7 Inhibitors on T Cell Functions

2020 ◽  
Vol 21 (17) ◽  
pp. 6118 ◽  
Author(s):  
Marianna Szczypka
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Splice Variants ◽  
Cell Activity ◽  
Cell Functions ◽  
Simultaneous Inhibition ◽  
And Function

Phosphodiesterase 7 (PDE7), a cAMP-specific PDE family, insensitive to rolipram, is present in many immune cells, including T lymphocytes. Two genes of PDE7 have been identified: PDE7A and PDE7B with three or four splice variants, respectively. Both PDE7A and PDE7B are expressed in T cells, and the predominant splice variant in these cells is PDE7A1. PDE7 is one of several PDE families that terminates biological functions of cAMP—a major regulating intracellular factor. However, the precise role of PDE7 in T cell activation and function is still ambiguous. Some authors reported its crucial role in T cell activation, while according to other studies PDE7 activity was not pivotal to T cells. Several studies showed that inhibition of PDE7 by its selective or dual PDE4/7 inhibitors suppresses T cell activity, and consequently T-mediated immune response. Taken together, it seems quite likely that simultaneous inhibition of PDE4 and PDE7 by dual PDE4/7 inhibitors or a combination of selective PDE4 and PDE7 remains the most interesting therapeutic target for the treatment of some immune-related disorders, such as autoimmune diseases, or selected respiratory diseases. An interesting direction of future studies could also be using a combination of selective PDE7 and PDE3 inhibitors.

scholarly journals USP52 regulates DNA end resection and chemosensitivity through removing inhibitory ubiquitination from CtIP

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ming Gao ◽  
Guijie Guo ◽  
Jinzhou Huang ◽  
Jake A. Kloeber ◽  
Fei Zhao ◽  
...  
Keyword(s):  
Parp Inhibition ◽  
Dependent Manner ◽  
Interacting Protein ◽  
Post Translational Modifications ◽  
Regulatory Complexity ◽  
Dna End Resection ◽  
End Resection

Abstract Human C-terminal binding protein (CtBP)–interacting protein (CtIP) is a central regulator to initiate DNA end resection and homologous recombination (HR). Several studies have shown that post-translational modifications control the activity or expression of CtIP. However, it remains unclear whether and how cells restrain CtIP activity in unstressed cells and activate CtIP when needed. Here, we identify that USP52 directly interacts with and deubiquitinates CtIP, thereby promoting DNA end resection and HR. Mechanistically, USP52 removes the ubiquitination of CtIP to facilitate the phosphorylation and activation of CtIP at Thr-847. In addition, USP52 is phosphorylated by ATM at Ser-1003 after DNA damage, which enhances the catalytic activity of USP52. Furthermore, depletion of USP52 sensitizes cells to PARP inhibition in a CtIP-dependent manner in vitro and in vivo. Collectively, our findings reveal the key role of USP52 and the regulatory complexity of CtIP deubiquitination in DNA repair.

scholarly journals Role of regulatory T cells in experimental autoimmune glomerulonephritis

2019 ◽  
Vol 316 (3) ◽  
pp. F572-F581 ◽  
Author(s):  
Stefanie Klinge ◽  
Karsten Yan ◽  
Daniel Reimers ◽  
Karen-Maria Brede ◽  
Joanna Schmid ◽  
...  
Keyword(s):  
T Cells ◽  
Crescentic Glomerulonephritis ◽  
Treg Cells ◽  
Peripheral Tolerance ◽  
Rapid Loss ◽  
Type Iv ◽  
Forkhead Box ◽  
Goodpasture Antigen ◽  
Experimental Autoimmune

Anti-glomerular basement membrane (anti-GBM) disease is characterized by antibodies and T cells directed against the Goodpasture antigen, the noncollagenous domain of the α3-chain of type IV collagen [α3(IV)NC1] of the GBM. Consequences are the deposition of autoantibodies along the GBM and the development of crescentic glomerulonephritis (GN) with rapid loss of renal function. Forkhead box protein P3 (Foxp3)+ regulatory T (Treg) cells are crucial for the maintenance of peripheral tolerance to self-antigens and the prevention of immunopathology. Here, we use the mouse model of experimental autoimmune GN to characterize the role of Treg cells in anti-GBM disease. Immunization of DBA/1 mice with α3(IV)NC1 induced the formation of α3(IV)NC1-specific T cells and antibodies and, after 8–10 wk, the development of crescentic GN. Immunization resulted in increased frequencies of peripheral Treg cells and renal accumulation of these cells in the stage of acute GN. Depletion of Treg cells during immunization led to enhanced generation of α3(IV)NC1-specific antibodies and T cells and to aggravated GN. In contrast, depletion or expansion of the Treg cell population in mice with established autoimmunity had only minor consequences for renal inflammation and did not alter the severity of GN. In conclusion, our results indicate that in anti-GBM disease, Treg cells restrict the induction of autoimmunity against α3(IV)NC1. However, Treg cells are inefficient in preventing crescentic GN after autoimmunity has been established.

scholarly journals Protein Phosphatase 2A Reactivates FOXO3a through a Dynamic Interplay with 14-3-3 and AKT

2010 ◽  
Vol 21 (6) ◽  
pp. 1140-1152 ◽  
Author(s):  
Amrik Singh ◽  
Min Ye ◽  
Octavian Bucur ◽  
Shudong Zhu ◽  
Maria Tanya Santos ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Transcriptional Activation ◽  
Protein Phosphatase ◽  
Nuclear Translocation ◽  
Akt Phosphorylation ◽  
Forkhead Box ◽  
Phosphatase 2A ◽  
And Function ◽  
Dynamic Interplay

Forkhead box transcription factor FOXO3a, a key regulator of cell survival, is regulated by reversible phosphorylation and subcellular localization. Although the kinases regulating FOXO3a activity have been characterized, the role of protein phosphatases (PP) in the control of FOXO3a subcellular localization and function is unknown. In this study, we detected a robust interaction between FOXO3a and PP2A. We further demonstrate that 14-3-3, while not impeding the interaction between PP2A and FOXO3a, restrains its activity toward AKT phosphorylation sites T32/S253. Disruption of PP2A function revealed that after AKT inhibition, PP2A-mediated dephosphorylation of T32/S253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of FOXO3a. Our findings reveal that distinct phosphatases dephosphorylate conserved AKT motifs within the FOXO family and that PP2A is entwined in a dynamic interplay with AKT and 14-3-3 to directly regulate FOXO3a subcellular localization and transcriptional activation.

scholarly journals Characterization of Strip1 Expression in Mouse Cochlear Hair Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Shasha Zhang ◽  
Ying Dong ◽  
Ruiying Qiang ◽  
Yuan Zhang ◽  
Xiaoli Zhang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Immunofluorescent Staining ◽  
Cochlear Hair Cells ◽  
Interacting Protein ◽  
Hearing Ability ◽  
Hearing Function ◽  
Mrna And Protein Expression ◽  
And Function

Striatin-interacting protein 1 (Strip1) is a core component of the striatin interacting phosphatase and kinase (STRIPAK) complex, which is involved in embryogenesis and development, circadian rhythms, type 2 diabetes, and cancer progression. However, the expression and role of Strip1 in the mammalian cochlea remains unclear. Here we studied the expression and function of Strip1 in the mouse cochlea by using Strip1 knockout mice. We first found that the mRNA and protein expression of Strip1 increases as mice age starting from postnatal day (P) 3 and reaches its highest expression level at P30 and that the expression of Strip1 can be detected by immunofluorescent staining starting from P14 only in cochlear HCs, and not in supporting cells (SCs). Next, we crossed Strip1 heterozygous knockout (Strip +/−) mice to obtain Strip1 homozygous knockout (Strip1−/−) mice for studying the role of Strip1 in cochlear HCs. However, no Strip1−/− mice were obtained and the ratio of Strip +/− to Strip1+/+ mice per litter was about 2:1, which suggested that homozygous Strip1 knockout is embryonic lethal. We measured hearing function and counted the HC number in P30 and P60 Strip +/− mice and found that they had normal hearing ability and HC numbers compared to Strip1+/+ mice. Our study suggested that Strip1 probably play important roles in HC development and maturation, which needs further study in the future.

scholarly journals Metabolic Controls on Epigenetic Reprogramming in Regulatory T Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Jingli Lu ◽  
Yan Liang ◽  
Haiyang Meng ◽  
Ailing Zhang ◽  
Junjie Zhao ◽  
...  
Keyword(s):  
Treg Cell ◽  
Metabolic Pathways ◽  
Cell Activation ◽  
Cell Metabolism ◽  
Cell Subset ◽  
Treg Cells ◽  
Cell Development ◽  
Epigenetic Alterations ◽  
Forkhead Box ◽  
And Function

Forkhead box protein 3 (Foxp3+)-expressing regulatory T (Treg) cells are a unique CD4+T cell subset that suppresses excessive immune responses. The epigenetic plasticity and metabolic traits of Treg cells are crucial for the acquisition of their phenotypic and functional characteristics. Therefore, alterations to the epigenetics and metabolism affect Treg cell development and function. Recent evidence reveals that altering the metabolic pathways and generation of metabolites can regulate the epigenetics of Treg cells. Specifically, some intermediates of cell metabolism can directly act as substrates or cofactors of epigenetic-modifying enzymes. Here, we describe the metabolic and epigenetic features during Treg cell development, and discuss how metabolites can contribute to epigenetic alterations of Treg cells, which affects Treg cell activation, differentiation, and function.

New Insights about Regulatory T Cells Distribution and Function with Exercise: The Role of Immunometabolism

2020 ◽  
Vol 26 (9) ◽  
pp. 979-990 ◽  
Author(s):  
Gilson P. Dorneles ◽  
Aline A.Z. dos Passos ◽  
Pedro R.T. Romão ◽  
Alessandra Peres
Keyword(s):  
T Cells ◽  
Chronic Diseases ◽  
Experimental Studies ◽  
Treg Cells ◽  
Metabolic Phenotype ◽  
Acid Oxidation ◽  
Low Grade ◽  
And Function ◽  
Low Grade Inflammation

A lack of physical activity is linked to the development of many chronic diseases through a chronic low-grade inflammation state. It is now well accepted that the immune system plays a central role in the development of several chronic diseases, including insulin resistance, type 2 diabetes, atherosclerosis, heart failure and certain types of cancer. Exercise elicits a strong anti-inflammatory response independently of weight loss and can be a useful non-pharmacologic strategy to counteract the low-grade inflammation. The CD4+CD25+CD127- FoxP3+ Regulatory T (Treg) cells are a unique subset of helper T-cells, which regulate immune response and establish self-tolerance through the secretion of immunoregulatory cytokines, such as IL-10 and TGF-β, and the suppression of the function and activity of many immune effector cells (including monocytes/macrophages, dendritic cells, CD4+ and CD8+ T cells, and Natural Killers). The metabolic phenotype of Tregs are regulated by the transcription factor Foxp3, providing flexibility in fuel choice, but a preference for higher fatty acid oxidation. In this review, we focus on the mechanisms by which exercise - both acute and chronic - exerts its antiinflammatory effects through Treg cells mobilization. Furthermore, we discuss the implications of immunometabolic changes during exercise for the modulation of Treg phenotype and its immunosuppressive function. This narrative review focuses on the current knowledge regarding the role of Treg cells in the context of acute and chronic exercise using data from observational and experimental studies. Emerging evidence suggests that the immunomodulatory effects of exercise are mediated by the ability of exercise to adjust and improve Tregs number and function.

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