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Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence

ABSTRACT: Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence

PROVIDER: PRJNA1032147 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26525812_1.fastq.gz	Fastqsanger.gz
	SRR26525812_2.fastq.gz	Fastqsanger.gz
	SRR26525813_1.fastq.gz	Fastqsanger.gz
	SRR26525813_2.fastq.gz	Fastqsanger.gz
	SRR26525814_1.fastq.gz	Fastqsanger.gz

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Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence

Project description:Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of WT (Lgmn+/+) mice following whole-brain irradiation. Lgmn knockout (Lgmn-/-) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP’s involvement in the antigen processing and presentation pathway and neuroinflammation. This was further confirmed by co-culturing Lgmn+/+ primary neurons with the conditioned media derived from irradiated Lgmn+/+ or Lgmn-/- primary microglia. Furthermore, esomeprazole inhibited the enzymatic activity of AEP and RIBI. These findings identified AEP as a critical factor of neuroinflammation in RIBI, highlighting the prospect of targeting AEP as a therapeutic approach.

2024-05-01 | GSE246261 | GEO

Wild-type P53 proteolytic inactivation by asparagine endopeptidase promotes glioblastoma progression

Project description:Wild-type P53 proteolytic inactivation by asparagine endopeptidase promotes glioblastoma progression

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Asparagine regulates RIG-I stability to suppress anti-tumor immunity in bladder cancer

Project description:Tumor cells often employ many ways to restrain type I interferon (IFN-I) signaling to evade immune surveillance. However, whether cellular amino acid metabolism regulate this process remains unclear and its effects on antitumor immunity are relatively unexplored. Here, our study reports that asparagine generated by asparagine synthetase (ASNS) inhibits IFN-I signaling and promotes immune escape in bladder cancer. We further show that depletion of ASNS strongly limits in vivo tumor growth in a CD8+ T cell-dependent manner, thus boosting the immunotherapy efficacy. Moreover, clinically approved ASNase synergizes with anti-PD-1 therapy in suppressing tumor growth in mouse models of bladder cancer. Mechanistically, asparagine intensifies the interaction of E3 ligase CBL and RIG-I, promoting K48-linked polyubiquitination and degradation of RIG-I, thus suppressing RIG-I mediated IFN signaling and anti-tumor immune response. Clinically, ASNS is overexpressed in muscle-invasive bladder cancer and correlated with poor response of immunotherapy. Together, our findings uncover asparagine as a natural metabolite to modulate RIG-I-mediated IFN-I signaling, providing the basis for developing the combinatorial use of ASNase and anti-PD-1 for bladder cancer.

2025-03-19 | GSE270353 | GEO

Asparagine availability controlsgerminal centre B cell homeostasis

Project description:Germinal centre (GC) B cells proliferate at some of the highest rates of any mammalian cell. Yet the metabolic processes which enable this are poorly understood. We performed integrated metabolomic and transcriptomic profiling of GC B cells, and found that asparagine metabolism is highly upregulated. Asparagine is conditionally essential to B cells, and its synthetic enzyme, asparagine synthetase (ASNS) is markedly upregulated following their activation, through the integrated stress response sensor general control non-derepressible 2 (GCN2). When Asns is deleted, B cell survival in low asparagine conditions is severely impaired. Using stable isotope tracing, we found that metabolic adaptation to the absence of asparagine requires ASNS, and that the synthesis of nucleotides is particularly sensitive to asparagine deprivation. Conditional deletion of Asns in B cells selectively impairs GC formation, associated with a reduction in RNA synthesis rates. Finally, removal of environmental asparagine by asparaginase was found to also severely compromise the GC reaction.

2024-04-03 | GSE228845 | GEO

Rapamycin mitigates Valproic Acid-induced teratogenicity in human and animal models by suppressing AP-1-mediated senescence

Project description:Rapamycin mitigates Valproic Acid-induced teratogenicity in human and animal models by suppressing AP-1-mediated senescence

| PRJNA1010729 | ENA

Asparagine availability controls B cell homeostasis

Project description:Study of the effects of asparagine deprivation on germinal centre B cells.

2025-03-21 | GSE277338 | GEO

Blockade of Asparagine Endopeptidase Inhibits Cancer Metastasis.

Project description:Asparagine endopeptidase (AEP), also called legumain, is highly expressed in various solid tumors, promoting cancer cell invasion, migration, and metastasis. It has been proposed to be a prognostic marker and therapeutic target for cancer treatment. However, an effective nonpeptide, small-molecule inhibitor against this protease has not yet been identified. Here we show that a family of xanthine derivatives selectively inhibit AEP and suppress matrix metalloproteinase (MMP) cleavage, leading to the inhibition of cancer metastasis. Through structure-activity relationship (SAR) analysis, we obtained an optimized lead compound (38u) that represses breast cancer invasion and migration. Chronic treatment of nude mice, which had been inoculated with MDA-MB-231 cells, with inhibitor 38u via oral administration robustly inhibits breast cancer lung metastasis in a dose-dependent manner, associated with blockade of MMP-2 by AEP. Therefore, our study supports that 38u might act as a potent and specific AEP inhibitor useful for cancer treatment.

| S-EPMC5871875 | biostudies-literature

Sex-specific effects of exogenous asparagine on colorectal tumor growth, 17β-estradiol levels, and aromatase

Project description:Sex-related differences in asparagine metabolism are associated with cancer prognosis. However, the effect of exogenous asparagine on colorectal cancer (CRC) growth in men and women remain unclear. This study aims to understand the relationship between exogenous asparagine supplementation and 17β-estradiol levels and to elucidate mechanisms underlying sex-dependent signaling during CRC development. We administered asparagine intraperitoneally to tumor-bearing immunodeficient male and female Rag2/Il2RG (R2G2) mice. Asparagine supplementation caused a significant increase in tumor asparagine levels in both the tumor-bearing male and female R2G2 mice but increased serum estradiol levels and suppressed tumor growth in female R2G2 mice only. Additionally, we combined transcriptome, metabolome and immunochemical analyses and found that intraperitoneal asparagine treatment induced sex-dependent intra-tumoral metabolic changes to asparagine, aspartate, glutamine and glutamate levels in CRC cells. We observed that in females, exogenous asparagine exerts a negative feed-back effect on de novo asparagine synthesis and is associated with the activation of a sub-population of macrophages that may secrete 17β-estradiol via an aromatase or cytochrome P450 family 19 (CYP19)-dependent mechanism, resulting in improved tumor-specific survival. Conversely, in male mice, asparagine treatment augments tumor growth and is related to decreased numbers of macrophages, reduction in CYP19-mediated 17β-estradiol secretion leading to worsened tumor-specific survival. Overall, our results reveal a novel and sex-specific role for exogenous asparagine during cancer progression and underscores the importance of understanding mechanisms that control asparagine biosynthesis.

2025-12-23 | GSE314476 | GEO

Gene expression profiling of leukemia cells following asparagine depletion

Project description:We will report the gene expression changes following asparagine depletion in human ALL cell line, RS4;11

2019-08-06 | GSE135420 | GEO

DL-endopeptidase changes in CD

Project description:Gut microbial DL-endopeptidase protects Crohn’s disease via NOD2 pathway

| PRJEB51945 | ENA