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Disruption of the moonlighting function of CTF18 in a patient with T-lymphopenia

ABSTRACT: Disruption of the moonlighting function of CTF18 in a patient with T-lymphopenia

PROVIDER: PRJNA1222996 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32324393_1.fastq.gz	Fastqsanger.gz
	SRR32324393_2.fastq.gz	Fastqsanger.gz
	SRR32324394_1.fastq.gz	Fastqsanger.gz
	SRR32324394_2.fastq.gz	Fastqsanger.gz
	SRR32324395_1.fastq.gz	Fastqsanger.gz

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Disruption of the moonlighting function of CTF18 in a patient with T-lymphopenia

Project description:Newborn screening for immunodeficiency has led to the identification of numerous cases for which the causal etiology is unknown. Here we report the diagnosis of T lymphopenia of unknown etiology in a male proband. Whole exome sequencing (WES) nominated as the top candidate variants, missense mutations in CHTF18 that were inherited in an autosomal recessive manner. CTF18, encoded by the CHTF18 gene, is a component of a secondary clamp loader, which is primarily thought to function by promoting DNA replication. We determined that the patient’s variants in CHTF18 (CTF18 R751W and E851Q) were damaging to function and severely attenuated the capacity of CTF18 to support hematopoiesis and lymphoid development, strongly suggesting that they were responsible for his T lymphopenia; however, the attenuation of CTF18 function appeared to be unrelated to its role as a clamp loader. DNA-damage, expected when replication is impaired, was not evident by expression profiling in murine Chtf18 mutant hematopoietic stem and progenitor cells (HSPC), nor was development of Ctf18-deficient progenitors rescued by p53 loss. Instead, we observed an expression signature suggesting disruption of HSPC positioning and migration. Indeed, the positioning of HSPC in ctf18 morphant zebrafish embryos was perturbed, suggesting that HSPC function was impaired through disrupted positioning in hematopoietic organs. Accordingly, we propose that T lymphopenia in our patient resulted from disturbed cell-cell contacts and migration of HSPC, caused by a non-canonical function of CHTF18 in regulating gene expression.

2025-02-12 | GSE289457 | GEO

Disruption of the moonlighting function of CTF18 in a patient with T-lymphopenia.

Project description:IntroductionNewborn screening for immunodeficiency has led to the identification of numerous cases for which the causal etiology is unknown.MethodsHere we report the diagnosis of T lymphopenia of unknown etiology in a male proband. Whole exome sequencing (WES) was employed to nominate candidate variants, which were then analyzed functionally in zebrafish and in mice bearing orthologous mutations.ResultsWES revealed missense mutations in CHTF18 that were inherited in an autosomal recessive manner. CTF18, encoded by the CHTF18 gene, is a component of a secondary clamp loader, which is primarily thought to function by promoting DNA replication. We determined that the patient's variants in CHTF18 (CTF18 R751W and E851Q) were damaging to function and severely attenuated the capacity of CTF18 to support hematopoiesis and lymphoid development, strongly suggesting that they were responsible for his T lymphopenia; however, the function of CTF18 appeared to be unrelated to its role as a clamp loader. DNA-damage, expected when replication is impaired, was not evident by expression profiling in murine Chtf18 mutant hematopoietic stem and progenitor cells (HSPC), nor was development of Ctf18-deficient progenitors rescued by p53 loss. Instead, we observed an expression signature suggesting disruption of HSPC positioning and migration. Indeed, the positioning of HSPC in ctf18 morphant zebrafish embryos was perturbed, suggesting that HSPC function was impaired through disrupted positioning in hematopoietic organs.DiscussionAccordingly, we propose that T lymphopenia in our patient resulted from disturbed cell-cell contacts and migration of HSPC, caused by a non-canonical function of CHTF18 in regulating gene expression.

| S-EPMC11868726 | biostudies-literature

Nucleus-Translocated GCLM Promotes Chemoresistance in Colorectal Cancer through a Moonlighting Function

Project description:Nucleus-Translocated GCLM Promotes Chemoresistance in Colorectal Cancer through a Moonlighting Function

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‘Moonlighting’ cytoplasmic proteins

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Nucleus-Translocated GCLM Promotes Chemoresistance in Colorectal Cancer through a Moonlighting Function

Project description:Emerging evidence indicates that metabolic enzymes perform moonlighting functions during tumor progression, including the modulation of chemoresistance. However, the underlying mechanisms of these functions remain elusive. In this study, utilizing a genome-scale metabolic CRISPR-Cas9 knockout library screen, we observed that loss of Glutamate-cysteine ligase modifier subunit (GCLM), a rate-limiting enzyme in glutathione biosynthesis, noticeably heightens the sensitivity of colorectal cancer (CRC) cells to platinum-based chemotherapy. Mechanistically, we unveil a noncanonical mechanism through which nuclear GCLM competitively interacts with NF-kappa-B-repressing factor (NKRF), a known inhibitor of NF-κB signaling, to promote NF-κB activity and subsequently facilitate chemoresistance. In response to platinum drug treatment, P38 phosphorylates GCLM at T17, resulting in its recognition by importin a5 and subsequent nuclear translocation. Furthermore, elevated expression of nuclear GCLM is evident in CRC tissues and correlates with poor prognosis and heightened P38 activity. Overall, our findings shed light on the essential nonmetabolic role and posttranslational regulatory mechanism of GCLM in enhancing NF-κB activity and subsequent chemoresistance.

2024-01-28 | GSE254136 | GEO

Disruption of SUV39H1-mediated H3K9 methylation sustains CAR T cell function

Project description:Disruption of SUV39H1-mediated H3K9 methylation sustains CAR T cell function

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ZFP36 disruption is insufficient to enhance the function of mesothelin-targeting human CAR-T cells

Project description:Loss of inflammatory effector function, such as cytokine production and proliferation, is a fundamental driver of failure in T cell therapies against solid tumors. Here, we used CRISPR/Cas9 to genetically disrupt ZFP36, an RNA binding protein that regulates the stability of mRNAs involved in T cell inflammatory function, such as the cytokines IL2 and IFNγ, in human T cells engineered with a clinical-stage mesothelin-targeting CAR to determine whether its disruption could enhance antitumor responses. ZFP36 disruption slightly increased antigen-independent activation and cytokine responses but did not enhance overall performance in vitro or in vivo in a xenograft tumor model with NSG mice. While ZFP36 disruption does not reduce the function of CAR-T cells, these results suggest that singular disruption of ZFP36 is not sufficient to improve their function and may benefit from a multiplexed approach.

2024-02-14 | GSE234866 | GEO

Disruption of developmental enhancer and PRC2 function by K27M in childhood glioma

Project description:Disruption of developmental enhancer and PRC2 function by K27M in childhood glioma

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Virulence factors produced by Staphylococcus aureus biofilms have a moonlighting function contributing to biofilm integrity

Project description:We comprehensively profiled intracellular and ECM proteomes of S. aureus flow biofilms and complemented these data by metabolic footprint analysis and phenotypic assays. We show that S. aureus biofilms produce high amounts of secreted, moonlighting virulence factors stabilizing the ECM. Mechanistically, we propose that these alkaline virulence factors get protonated in an acidified ECM (due to the release of acids upon fermentation) mediating electrostatic interactions with anionic cell surface components and metabolites, which leads to cell aggregation and ECM stabilization.

2019-03-13 | PXD011157 | Pride

Time-restricted feeding prevents deleterious metabolic effects of circadian disruption through epigenetic control of β-cell function [ATACseq]

Project description:Circadian rhythm disruption (CD) is associated with dysregulation of glucose homeostasis and Type 2 diabetes mellitus (T2DM). While the link between CD and T2DM remains unclear, there is accumulating evidence that disruption of fasting/feeding cycles mediates CD-induced metabolic dysfunction. Herein we utilized an approach encompassing analysis of behavioral, physiological, transcriptomic, and single-cell epigenomic effects of CD and consequences of restoration of fasting/feeding cycles through time-restricted feeding (tRF) in mice. Results show that CD perturbs glucose homeostasis through disruption of pancreatic β-cell function and loss of circadian β-cell transcriptional and epigenetic control. In contrast, restoration of fasting/feeding cycle prevented CD-mediated metabolic dysfunction by reestablishing circadian regulation of glucose tolerance, β-cell function, β-cell transcriptional profile, and reestablishment of proline and acidic amino acid-rich basic leucine zipper (PAR-bZIP) transcription factor activity in β-cells. This study provides mechanistic insights into beneficial effects of tRF and its role in prevention of β-cell failure in T2DM.

2021-11-24 | GSE182936 | GEO

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