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Palmitoylation prevents B7-H4 lysosomal degradation sustaining tumor immune evasion

ABSTRACT: Palmitoylation prevents B7-H4 lysosomal degradation sustaining tumor immune evasion

PROVIDER: PRJNA1136969 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29867447_1.fastq.gz	Fastqsanger.gz
	SRR29867447_2.fastq.gz	Fastqsanger.gz
	SRR29867448_1.fastq.gz	Fastqsanger.gz
	SRR29867448_2.fastq.gz	Fastqsanger.gz
	SRR29867449_1.fastq.gz	Fastqsanger.gz

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B7-H4 post-translational modifications

Project description:B7-H4 functions as an immune checkpoint in the tumor microenvironment (TME). However, the post-translational modification (PTM) of B7-H4 and its translational potential in cancer remains incompletely understood. We found that ZDHHC3, a zinc finger DHHC-type palmitoyltransferase, palmitoylates B7-H4 at Cys130 in breast cancer cells, preventing its lysosomal degradation and sustaining B7-H4-mediated immunosuppression. Knockdown of ZDHHC3 in tumors resulted in robust anti-tumor immunity and reduced tumor progression in murine models. Moreover, abemaciclib, a CDK4/6 inhibitor, primed lysosome activation and promoted lysosomal degradation of B7-H4 independently of the tumor cell cycle. Treatment with abemaciclib resulted in T cell activation and mitigated B7-H4-mediated immune suppression via inducing B7-H4 degradation in preclinical tumor models. Thus, B7-H4 palmitoylation is an undocumented PTM controlling B7-H4 protein stability and abemaciclib may be repurposed to enhance B7-H4 degradation, thereby treating patients with B7-H4+ tumors.

2025-02-14 | PXD054393 | Pride

Palmitoylation prevents B7-H4 lysosomal degradation sustaining tumor immune evasion

Project description:To investigate the function of CDK4/6 inhibitor- Abemaciclib on lysosome function.

2025-02-13 | GSE272492 | GEO

Analysis of Wild Type and B7-H4-/- leukemia initial cells Transcriptomes

Project description:The goal of this study are to find the abonormally expressed genes of B7-H4-/- leukemia inital cells in MLL-AF9 induced AML mice by RNA-seq analysis.Methods: Lin- festival liver cells were isolated from WT and B7-H4-null mice and infected with MLL-AF9 retroviruses, then transplanted to the lethally irradiated recipient mice. When AML developed, we isolated the YFP+/Mac-1+/c-Kit+ bone marrow cells by FACS and and then made the RNA-sequence using Illumina. Results: We identified 27180 transcripts in wild type and B7-H4-/- leukemia initial cells. 572 transcripts showed differential expression between the WT and B7-H4−/− LICs, with a fold change ≥1.5 and p value <0.01. 271 transcripts were downregulated and 241 transcripts were upregulated.

2018-10-25 | GSE89161 | GEO

B7-H4 regulates β cell mass and insulin secretion by modulating cholesterol metabolism

Project description:Chronic islet inflammation is a hallmark of type 2 diabetes (T2D) and involves in the dysfunction of β cells. However, how β cells participate in this process remains unclear. Here, we report that the immune checkpoint molecule B7-H4(B7S1, B7x, VTCN1) expressed in β cells is critical to maintain β cell mass and insulin secretion. Lesion of B7-H4 in β cells results in glucose intolerance due to less β cell mass and deficient insulin secretion with upregulated cytokines and activated signal transducer and activator of transcription 5 (Stat5) signaling, while overexpression of B7-H4 in β cells ameliorates glucose intolerance in high-fat diet (HFD)-treated mice. Mechanistically, B7-H4 deficiency actives the Stat5 signaling, which inhibits the expression of Apolipoprotein F (ApoF), leading to reduced cholesterol efflux and accumulated cholesterol in β cells, thereby impairing the insulin processing and secretion. Inhibiting Stat5 activity or overexpression of ApoF in β cells can rescue the glucose intolerance and insulin secretion deficiency in β-cell-specific B7-H4 knockout (B7-H4 cKO) mice. Our study demonstrates that β cell expressed immune checkpoint molecule B7-H4 is essential for islet immune homeostasis and β cell function maintenance, and for the first time unravels the mechanism by which B7-H4 regulates insulin secretion through regulating cholesterol metabolism via Stat5 signaling, which may shed new light on the development of novel strategies for T2D treatment.

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Pancreatic epithelial IL-17/IL-17RA signaling drives B7-H4 to promote tumorigenesis

Project description:IL-17 is required for the initiation and progression of pancreatic cancer, particularly in the context of inflammation, as previously shown by genetic and pharmacological approaches. The cellular compartment and downstream molecular mediators of IL-17-mediated pancreatic tumorigenesis have not been fully identified. We interrogated the cellular compartment required by generating transgenic animals with Interleukin 17 receptor A (IL-17RA) genetically deleted from the pancreatic epithelial compartment vs. the hematopoietic compartment via generation of IL-17RA-deficient (IL17-RA-/-) bone marrow chimeras, in the context of embryonically activated or inducible Kras. Deletion of IL-17RA from the pancreatic epithelial compartment, but not from hematopoietic, resulted in delayed premalignant lesions initiation and progression and increased CD8+ cytotoxic T cells infiltration to the tumor microenvironment. Absence of IL-17RA in the pancreatic compartment affected transcriptional profiles of epithelial cells, modulating stemness and immunological pathways. Interestingly, B7-H4, a known inhibitor of T cell activation encoded by the gene Vtcn1, was the most upregulated checkpoint molecule via IL17 early during pancreatic tumorigenesis, and its genetic deletion delayed pancreatic premalignant lesions development and reduced immunosuppression. We reveal pancreatic epithelial IL-17RA requirement for pancreatic tumorigenesis by reprogramming the immune pancreatic landscape which is partially orchestrated by regulation of B7-H4.

2024-04-15 | GSE264054 | GEO

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Project description:VTCN1/B7-H4 is expressed in human embryonic stem cells (hESC) to an in vitro model of primitive trophoblast (TB) and first trimester but not term human placenta and that primitive trophoblast may be uniquely susceptible to certain pathogens.

2023-03-13 | GSE227096 | GEO

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2023-03-13 | GSE227094 | GEO

ZDHHC20-Mediated S-Palmitoylation of YTHDF3 Stabilizes MYC mRNA to Promote Pancreatic Cancer Progression

Project description:Post-translational modifications of malignant transformation and tumor maintenance in pancreatic ductal adenocarcinoma (PDAC) in the context of KRAS signaling remains largely unexplored. Here, we used the KPC mouse model to examine the effect of palmitoylation on pancreatic cancer progression. ZDHHC20, upregulated by KRAS, is abnormally overexpressed and associated with poor prognosis in patients with pancreatic cancer. Dysregulation of ZDHHC20 promotes pancreatic cancer progression in a palmitoylation-dependent manner. ZDHHC20 inhibits lysosomal localization and degradation of YTHDF3 through S-palmitoylation of Cys474, which can result in abnormal accumulation of the oncogenic product MYC and thereby promote the malignant phenotypes of cancer cells. Further, we designed a biologically active YTHDF3-derived peptide to competitively inhibit YTHDF3 palmitoylation mediated by ZDHHC20, which in turn downregulated MYC expression and inhibited the progression of KRAS mutant pancreatic cancer. Thus, these findings highlight the therapeutic potential of targeting the ZDHHC20-YTHDF3-MYC signaling axis in pancreatic cancer.

2024-04-22 | GSE235516 | GEO

Exiguobacterium antarcticum B7 strain:B7

Project description:Exiguobacterium antarcticum B7 strain:B7 Genome sequencing

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