Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of FOXP3 by Stapled Alpha-Helical Peptides Dampens Regulatory T Cell Function

ABSTRACT: Despite continuing advances in the development of novel cellular-, antibody-, and chemotherapeutic-based strategies to enhance immune reactivity, the presence of regulatory T cells (Tregs) remains a complicating factor to their clinical efficacy. To overcome dosing limitations and off-target effects from antibody-based Treg deletional strategies, we investigated the ability of hydrocarbon stapled alpha-helical (SAH) peptides to target FOXP3, the master transcription factor regulator of Treg development, maintenance, and suppressive function. Using the crystal structure of the FOXP3 homodimer as a guide, we developed SAHs in the likeness of a portion of the native FOXP3 antiparallel coiled-coil homodimerization domain (SAH-FOXP3) to block this key FOXP3 protein-protein interaction (PPI) through molecular mimicry. We show that lead SAH-FOXP3s bind FOXP3, are cell permeable, non-toxic to T cells, induce dose-dependent transcript and protein level alterations of FOXP3 target genes, impede Treg function, and lead to Treg gene expression changes in vivo consistent with Foxp3 dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE201116 | GEO | 2022/09/29

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Inhibition of FOXP3 by Stapled Alpha-Helical Peptides Dampens Regulatory T Cell Function

Project description:Inhibition of FOXP3 by Stapled Alpha-Helical Peptides Dampens Regulatory T Cell Function

| PRJNA828456 | ENA

Nemo-like kinase drives Foxp3 stability and is critical for maintenance of immune tolerance by regulatory T cells

Project description:The Foxp3 transcription factor is a crucial determinant of both regulatory T (TREG) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in TREG cells can be regulated by a TGFβ Activated Kinase 1 (TAK1)-Nemo Like Kinase (NLK) signaling pathway. NLK interacts with Foxp3 in TREG cells and directly phosphorylates Foxp3 on multiple serine residues. This phosphorylation results in stabilization of Foxp3 protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase, resulting in both reduced ubiquitination and proteasome-mediated degradation. Conditional TREG cell NLK-knockout (NLKTREG) results in decreased TREG cell-mediated immunosuppression in vivo and NLK-deficient TREG cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through stabilization of protein levels, thereby maintaining TREG cell suppressive function. Pharmacological manipulation of this phosphorylation-ubiquitination axis may provide therapeutic opportunities for regulating TREG cell function, for example during cancer immunotherapy.

2019-09-02 | PXD011164 | Pride

A cell-permeable stapled peptide inhibitor of the estrogen receptor/coactivator interaction

Project description:We and others have proposed that coactivator binding inhibitors, which block the interaction of estrogen receptor and steroid receptor coactivators, may represent a potential class of new breast cancer therapeutics. The development of coactivator binding inhibitors has been limited, however, because many of the current molecules which are active in in vitro and biochemical assays are not active in cell-based assays. Our goal in this work was to prepare a coactivator binding inhibitor active in cellular models of breast cancer. To accomplish this, we used molecular dynamics simulations to convert a high-affinity stapled peptide with poor cell permeability into R4K1, a cell-penetrating stapled peptide. R4K1 displays high binding affinity for estrogen receptor ɑ, inhibits the formation of estrogen receptor/coactivator complexes, and distributes throughout the cell with a high percentage of nuclear localization. R4K1 represses native gene transcription mediated by estrogen receptor ɑ and inhibits proliferation of estradiol-stimulated MCF-7 cells. Using RNA-Seq, we demonstrate that almost all of the effects of R4K1 on global gene transcription are estrogen receptor-associated. This chemical probe provides a significant proof-of-concept for preparing cell-permeable stapled peptide inhibitors of the estrogen receptor/coactivator interaction.

2018-01-09 | GSE108308 | GEO

Stapled peptide inhibitors of RAB25 target context-specific phenotypes in cancer

Project description:The Ras-family small GTPase RAB25 is involved in numerous aspects of endosomal protein trafficking and cell polarity. Recent evidence has established a role for RAB25, as well as related RAB-family and effector proteins, in oncogenic signaling, highlighting the need for chemical probes targeting this class of proteins. Here we report the development of all-hydrocarbon stabilized peptides targeting RAB25 derived from the RAB-binding FIP-family of proteins. Relative to unmodified FIP peptides, optimized stapled peptides show markedly increased structural stability, binding affinity, cell permeability and inhibition of RAB25:FIP complex formation. RAB25 expression has been shown to promote both pro- and anti-oncogenic phenotypes in specific cellular contexts. Stapled peptide RFP14 treatment of breast and ovarian cancer cell lines, in which RAB25 is pro-oncogenic, inhibited migration and proliferation in a RAB25-dependent manner. In contrast, treatment of a triple-negative breast cancer cell line in which RAB25 is tumor suppressive augmented proliferation and migration. Gene expression (RNA Seq) profiling identified significantly altered transcripts in response to RAB25 expression in ovarian cancer cells, and treatment with the optimized stapled peptide RFP14 reversed this expression profile. These data validate first-in-class chemical probes targeting RAB-family proteins and support the role of RAB25 in regulating context-specific oncogenic phenotypes.

2017-07-18 | GSE101528 | GEO

Suppression of p53 response by blocking p53-Mediator binding with a stapled peptide

Project description:DNA-binding transcription factors (TFs) have been challenging to target with molecular probes. Many TFs function in part through interaction with Mediator; we sought to block p53 function by disrupting the p53-Mediator interaction. Through rational design and activity-based screening, we characterized a stapled peptide, with functional mimics of both p53 activation domains, that selectively disrupted p53- and Mediator-dependent transcription in vitro. This “bivalent peptide” also suppressed p53 transcriptional response in human cancer cells. Our strategy circumvents the TF and instead targets the TF-Mediator interface, with desired transcriptional outcomes. Different TFs target Mediator through different subunits, suggesting this strategy could be generalizable.

2022-04-05 | GSE193418 | GEO

Suppression of p53 response by blocking p53–Mediator binding with a stapled peptide

2020-08-01 | GSE135870 | GEO

Chromatin immunoprecipitation of Foxp3 in mouse T-cell hybridoma cells

Project description:The forkhead transcription factor Foxp3 is essential for the development of CD4+CD25+ regulatory T (Treg) cells and prevention of autoimmunity, but how it controls the Treg gene expression program is not understood. We describe here genome-wide location and expression data that identify Foxp3 target genes and report that many Foxp3 target genes are key modulators of T cell activation and function. Remarkably, the predominant effect of Foxp3 binding is to suppress the activation of target genes upon T cell stimulation. Foxp3 suppression of its targets appears to be crucial for the normal function of Treg cells because overactive variants of some target genes are known to be associated with autoimmune disease.

2007-01-27 | E-TABM-154 | biostudies-arrayexpress

Human Treg LC-MSMS - Foxp3 drives oxidative phosphorylation and protection from lipotoxicity

Project description:Regulatory T cells (Treg) have been shown to adopt a catabolic metabolic programme with increased capacity for fatty acid oxidation fuelled oxidative phosphorylation (OXPHOS). The role of Foxp3 in this metabolic shift is poorly understood. Here we show that Foxp3 was sufficient to induce a significant increase in the spare respiratory capacity of the cell, the extra OXPHOS capacity available to a cell to meet increased demands on energy in response to work. Foxp3-expressing cells were enhanced in their ability to utilise palmitate for respiration and, in addition, the activity of electron transport complexes I, II and IV were enhanced following Foxp3 expression. Foxp3 also imparts a selective advantage in ATP generation capacity, one that might be exploited as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a quantitative proteomics study to compare the contribution of TGFβ and the transcription factor Foxp3 to the Treg proteome. We used quantitative mass spectrometry to examine differences between proteomes of nuclear and cytoplasmic Foxp3-containing CD4+ T cells from various sources with Foxp3- activated CD4 T cells, as well as Treg from human peripheral blood. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 expression is associated with a significant up regulation of several members of the mitochondrial electron transport chain. Not only does Foxp3 influence genes directly concerned with immune function, but also with the energy generating functions of Treg.

2017-02-15 | PXD001906 | Pride

Canonical Wnt signaling negatively modulates T regulatory cell function

Project description:Foxp3 is crucial for both the development and function of regulatory T cells (Treg),however the post-translational mechanisms regulating Foxp3 transcriptional output remain poorly defined. Here, we demonstrate that TCF1 and Foxp3 interact in the nucleus of Treg, and that active Wnt-signaling disrupts Foxp3 transcriptional activity. Utilizing a global ChIP-seq comparison we demonstrate considerable overlap between Foxp3 and Wnt target genes in Treg. Activation of Wnt signaling significantly reduces Treg-mediated suppression both in vitro and in vivo, while disruption of Wnt signaling in Treg enhances their suppressive capacity. Activation of effector T cells increases Wnt3a production, and Wnt3a levels were found to be greatly increased in mononuclear cells isolated from synovial fluid versus peripheral blood of arthritis patients. We propose a model in which Wnt produced by activated mononuclear cells under inflammatory conditions represses Treg function allowing a productive immune response, but if uncontrolled could lead to the development of autoimmunity. Beta catenin ChIP-seq in Treg

2013-07-26 | E-GEOD-49199 | biostudies-arrayexpress

A genome-wide CRISPR screen reveals a role for the non-canonical nucleosome remodeling BAF complex in Foxp3 expression and regulatory T cell function

Project description:Regulatory T cells (Treg) play a pivotal role in suppressing auto-reactive T cells and maintaining immune homeostasis. Treg development and function are dependent on the transcription factor Foxp3. Here we performed a genome-wide CRISPR loss-of-function screen to identify Foxp3 regulators in mouse primary Treg cells. Foxp3 regulators were enriched in genes encoding subunits of the SWI/SNF nucleosome remodeling and SAGA chromatin modifying complexes. Among the three SWI/SNF-related complexes, the Brd9-containing non-canonical (nc)BAF complex promoted Foxp3 expression, whereas the PBAF complex was repressive. Chemical-induced degradation of Brd9 led to reduced Foxp3 expression and reduced Treg function in vitro. Brd9 ablation compromised Treg function in inflammatory disease and tumor immunity in vivo. Furthermore, Brd9 promoted Foxp3 binding and expression of a subset of Foxp3 target genes. Our findings provide an unbiased analysis of the genetic networks regulating Foxp3 and reveal ncBAF as a target for therapeutic manipulation of Treg function.

2020-07-07 | GSE129846 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data