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CD28-Targeted Enzyme-Responsive Conformation-Switching Peptide Self-Assembly for Selective T-cell acute lymphoblastic leukemia (T-ALL) Therapy

ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with limited targeted therapies. CD28, a costimulatory receptor aberrantly overexpressed on T-ALL cells, presents a promising underexplored therapeutic target. In this study, we developed a modular enzyme-responsive self-assembling peptide, SAp-CD28, designed to selectively target CD28 and undergo receptor-mediated self-assembly in the tumor microenvironment. Upon dephosphorylation by overexpressed phosphatases, SAp-CD28 transitions from an α-helix to a β-sheet/β-turn rich structure, facilitating the formation of nano-oligomers that engage CD28 and activate cytotoxic pathways. Transcriptomic profiling revealed two key mechanisms: PLCγ1 pathway degradation and Akt signaling suppression, leading to calcium overload, cytoskeletal collapse, and necrotic cell death. Besides, confocal imaging suggested that the peptide self-assembly can enter the nucleus and disrupt it. In Jurkat xenograft models, SAp-CD28 demonstrated potent antitumor activity, and its combination with cytarabine resulted in near-complete tumor suppression, highlighting its potential for T-ALL treatment. This work introduces a CD28-targeted, enzyme-activated nanotherapeutic strategy that synergizes biochemical and mechanical mechanisms to selectively eliminate T-ALL cells. This multi-mechanistic tumor-killing strategy can also be extended to inspire therapeutic approaches for other diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE322735 | GEO | 2026/04/30

REPOSITORIES: GEO

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CD28-Targeted Enzyme-Responsive Conformation-Switching Peptide Self-Assembly for Selective T-cell acute lymphoblastic leukemia (T-ALL) Therapy

Project description:CD28-Targeted Enzyme-Responsive Conformation-Switching Peptide Self-Assembly for Selective T-cell acute lymphoblastic leukemia (T-ALL) Therapy

| PRJNA1431380 | ENA

Proteolytic-Resistant Self-Assembling Peptide Nanofibers Combat Specific Bacterial Infections via Trap-and-Kill

Project description:<p>The rise in global antibiotic resistance highlights the urgent need for effective antimicrobial agents. Antimicrobial peptides (AMPs) offer a potential solution to combat bacterial resistance. However, key challenges remain in addressing the limitations of current peptide drugs and biomaterials, such as narrow action modes, poor protease stability, and challenges in pathogen-specific targeting. This study introduces a series of multifunctional AMPs by integrating self-assembling systems. By regulating the length of cationic amino acid side chains, the optimized peptide Nhar was identified as a triple-functional candidate with the potential to solve these limitations. In aqueous solutions, Nhar self-assembles into nanofibers that trap pathogens, prevent their spread, and selectively kill Gram-positive bacteria. Nhar demonstrates remarkable protease resistance, retaining antimicrobial activity even under 10 mg/mL protease conditions. It induces bacterial death primarily through membrane disruption and multiple synergistic mechanisms. In a Staphylococcus aureus induced mouse bacteremia model, Nhar showed promising therapeutic potential. This work offer important insights for developing multifunctional antimicrobial therapies.</p>

2025-06-13 | MTBLS12424 | MetaboLights

Epo-Induced Erythroid Maturation Is Dependent on Plcγ1 Signaling

Project description:Erythropoiesis is a tightly regulated process. Development of red blood cells occurs through differentiation of hematopoietic stem cells into more committed progenitors and finally into erythrocytes. Binding of erythropoietin to its receptor (EpoR) is strictly required for erythropoiesis as it promotes survival and late maturation of erythroid progenitors. In vivo and in vitro studies have highlighted the requirement of EpoR signaling through Jak2 tyrosine-kinase and Stat5a/b as a central pathway. Here, we demonstrate that phospholipase C gamma 1 (Plcγ1) is activated downstream of EpoR/Jak2 independently of Stat5. Plcγ1-deficient proerythroblasts and erythroid progenitors exhibited strong impairment in differentiation and colony-forming potential. In vivo, suppression of Plcγ1 in immunophenotypically defined hematopoietic stem cells (Lin-Sca1+KIT+CD48-CD150+) severely reduced erythroid development. To identify Plcγ1 effector molecules involved in regulation of erythroid differentiation we assessed for changes on the level of transcription and DNA methylation after inactivation of Plcγ1. The single common downstream effector was H2AFY2, which encodes for the histone variant macroH2A2 (mH2A2). Suppression of macroH2A2 expression recapitulated the effects of Plcγ1 knockdown on erythroid maturation. Taken together, our findings identify Plcγ1 and its downstream target macroH2A2, as a “non-canonical” signaling pathway essential for erythroid differentiation.

2015-12-31 | GSE60087 | GEO

Gene expression in self-activating- and non-self-activationg CAR-T cells with CD28 or 4-1BB costimulatory domain.

Project description:We observed self-activation of SKM-CAR-T cells which target novel mesothelioma antigen. CAR-T with CD28 costimulatory domain showed signs of exhaustion while those with 4-1BB costimulatory domain did not. To elucidate molecules responsible for self-activation-induced exhaustion, we performed RNA-seq analysis of SKM-CAR-T cells with CD28 or 4-1BB and CD19-CAR-T cells with CD28 or 4-1BB.

2022-08-19 | GSE211352 | GEO

Phloem proteomics to identify small Open Reading Frame (sORF)-encoded peptides with a putative role in the control of flowering time in Arabidopsis

Project description:Phloem sap proteomic studies have previously revealed that phloem sap composition varies during development and upon floral induction. Specific proteins, lipids, messenger RNAs (mRNAs) and peptides have been shown to accumulate in different developmental stages. Peptides are of special interest since they have the potential to act as regulatory molecules controlling plant responses to environmental changes, such as salinity and water stress, plant-microbe interactions, and developmental changes. In this context, we have characterised Arabidopsis phloem exudates to identify proteins and peptides with potential to control flowering time, acting as signals fine tuning plant development. In this work, we present the proteomic profiles of the phloem sap samples during floral transition along with the identification of interesting proteins and peptides that could have a role in the control of flowering. Among those, we have described the abundance pattern of the sORF1511 peptide in the phloem sap, which varies upon floral induction. We show that sORF1511 overexpression affects bolting time and alters the expression of several genes involved in the control of flowering time.

2026-03-16 | GSE309559 | GEO

Zhang2020 - Draft metabolic reconstruction model of Atlantic cod liver generated from gadMorTrinity and iHepatocyte2322

Project description:This is an auto-generated model with COBRA Matlab toolbox. The gadMorTrinigy de novo Trinity transcript assembly and peptide sequences are available at https://doi.org/10.6084/m9.figshare.c.5168303.v2

2020-10-26 | MODEL2010090002 | BioModels

Phospholipase Cγ1 is crucially required for EpoR/JAK2 controlled erythropoietic differentiation.

Project description:Erythropoiesis is a multi-step process in which the development of red blood cells occurs through expansion and differentiation of hematopoietic stem cells (HSCs) into more committed progenitors. In vivo and in vitro studies have pointed out the major role of proximal erythropoietin receptor (EpoR) signaling through JAK2 tyrosine-kinase as a central regulator of erythropoiesis 1,2. However, little is known on more distant signalling pathways driving EPO/JAK2-induced differentiation of erythroid progenitors. Here, we demonstrate that phospholipase Cγ 1 (PLCγ1) is activated downstream of EpoR/JAK2 and is crucially required for differentiation of erythroid progenitor cells. In the absence of PLCγ1, erythroid progenitors exhibited dramatically impaired differentiation and colony-forming potential. To identify PLCγ1 effector molecules involved in regulation of erythroid differentiation we performed global gene expression and methylome analysis. In PLCγ1-deficient erythroid progenitors, profound changes in the landscape of DNA methylation and gene expression were observed. Taken together, our findings identify PLCγ1 as a central regulator in erythroid development and highlight its physiological relevance in development and maintenance of normal hematopoiesis.

2014-12-31 | GSE54223 | GEO

A Bidirectional Regulatory ACLY-NLRP3 Axis Integrates Metabolic and Inflammatory Signaling to Control NLRP3 Inflammasome Activation

Project description:<p _msttexthash='40138319' _msthash='7409'>The NLRP3 inflammasome is critical for host defense against bacterial infection and is involved in the pathogenesis of various inflammatory diseases. The aggregation of its sensor protein NLRP3 is a pivotal checkpoint for inflammasome activation. However, the regulatory mechanism of NLRP3 aggregation is not completely understood. Here, we identify the metabolic enzyme ATP-citrate lyase (ACLY) as a direct binding partner that constrains NLRP3 aggregation, membrane translocation and activation. We demonstrate that ACLY interacts with the NLRP3-PYD independently of its enzymatic function, thereby sterically hindering NLRP3 aggregation and suppressing inflammasome assembly. Paradoxically, we find that NLRP3 binding to ACLY inhibits ACLY’s enzymatic activity and remodels cellular metabolism, which counteracts the stimulatory effect of ACLY on NLRP3 inflammasome activation. This reciprocal interaction reveals an essential role of ACLY as a brake for NLRP3 aggregation, and also establishes NLRP3 as a metabolic checkpoint to regulate ACLY-mediated metabolism. Furthermore, we develop a peptide that disrupts the ACLY-NLRP3 interaction and promotes NLRP3 inflammasome activation, which enhances host defense against bacterial infection. Our work delineates a self-limiting circuit for immunometabolic crosstalk, positioning the ACLY-NLRP3 axis as a new therapeutic target for inflammasome-driven pathologies.</p>

2026-01-07 | MTBLS13400 | MetaboLights

Regulatory T cells enforce self-nonself discrimination by constraining conventional T cells of matched self-specificity during infection

Project description:During infections, Foxp3+ regulatory T (Treg) cells must control autoreactive conventional T (Tconv) cell responses against self-peptide antigens while permitting those against pathogen-derived “nonself” peptides. We sought to define the basis of this selectivity using mice in which Tregs reactive to a single prostate-specific self-peptide/MHC (self-pMHC) antigen, termed "C4", were selectively depleted ("C4ΔTEC" mice). We demonstrated that Tregs reactive to the C4 peptide were dispensable for the control of Tconv cells of matched antigen specificity at homeostasis but were required to control such Tconv cells and prevent fulminant prostatic autoimmunity following infection with the pathogen L monocytogenes engineered to express the C4 peptide ("Lm[C4]"). We performed the experiment outlined here to understand how the absence of C4-specific Treg cells in C4ΔTEC mice changes the phenotypic state of the C4-specific Tconv cells following Lm[C4] infection to drive autoimmunity. We found that C4-specific Tconv cells adopted preferential and differential cell states in both C4ΔTEC mice and wild-type mice that have C4-specific Treg cells. Specifically, gene expesion data revealed that C4-specific Tconv cells in wild-type mice preferentially adopted a non-proliferating effector state, while C4-specific Tconv in C4ΔTEC mice appeared as proliferating effector cells and proliferating central-memory cells.

2025-04-23 | GSE235974 | GEO

Cish inhibits CD8+ T cell immunity and disrupts proximal T cell receptor signaling

Project description:T cell receptor (TCR) signaling is a critical process in immunity to infectious disease and cancer. Recently, a genome-wide association study has implicated polymorphisms in the CISH locus with susceptibility to infectious diseases. However, the role of Cish in the immune responses and its molecular underpinnings remains unclear. Here we demonstrate that Cish deletion resulted in protection against viral infection and enhanced CD8+ T cell tumor immunity. Transcriptome profiling revealed a hyper-TCR activation signature in Cish-deficient CD8+ T cells. Subsequent analysis revealed an inhibitory role for Cish in PLCγ1 activation, ensuing Ca2+ release and downstream signaling. In the steady-state Cish was found to physically interact with PLCγ1, however, PLCγ1 was only found to be ubiquitinated after acute TCR stimulation in the presence of Cish. These data implicate Cish as a potent negative regulator of TCR signaling and T cell immunity to infection and cancer and may have significant clinical applications. 4 biological replicates from wild-type mice and 3 biological replicates from Cish knock-out (-/-) mice were analyzed.

2015-04-30 | E-GEOD-56328 | biostudies-arrayexpress

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