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Fam20c regulates the calpain proteolysis system through phosphorylating Calpasatatin to maintain cell homeostasis

ABSTRACT: Fam20c regulates the calpain proteolysis system through phosphorylating Calpasatatin to maintain cell homeostasis

PROVIDER: PRJNA976281 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24742130_1.fastq.gz	Fastqsanger.gz
	SRR24742130_2.fastq.gz	Fastqsanger.gz
	SRR24742131_1.fastq.gz	Fastqsanger.gz
	SRR24742131_2.fastq.gz	Fastqsanger.gz
	SRR24742132_1.fastq.gz	Fastqsanger.gz

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Fam20c regulates the calpain proteolysis system through phosphorylating Calpasatatin to maintain cell homeostasis

Project description:Background: The family with sequence similarity 20-member C (FAM20C) kinase, a Golgi casein kinase, which is responsible for phosphorylating the majority of the extracellular phosphoproteins within S-x-E/pS motifs, and is fundamentally associated with multiple biological processes to maintain cell proliferation, biomineralization, migration, adhesion, and phosphate homeostasis. In dissecting how FAM20C regulates downstream molecules and potential mechanisms, however, there are multiple target molecules of FAM20C, particularly many phenomena remain elusive, such as changes in cell-autonomous behaviors, incompatibility in genotypes and phenotypes, and others. Methods: Here, assay for transposase-accessible chromatin using sequencing (ATAC-seq), RNA sequencing (RNA-seq), proteomics, and phosphoproteomics were performed in Fam20c-dificient osteoblasts and to facilitate an integrated analysis and determine the impact of chromatin accessibility, genomic expression, protein alterations, signaling pathway, and post translational modifcations. Results: By combining ATAC-seq and RNA-seq, we identified TCF4 and Wnt signaling pathway as the key regulators in Fam20c-dificient cells. Further, we showed Calpastatin/Calpain proteolysis system as a novel target axis for FAM20C to regulate cell migration and F-actin cytoskeleton by integrated analysis of proteomics and phosphoproteomics. Furthermore, Calpastatin/Calpain proteolysis system could negatively regulate the Wnt signaling pathway. Conclusion: These observations implied that Fam20c knockout osteoblasts would cause cell homeostatic imbalance, involving changes in multiple signaling pathways in the conduction system.

2023-09-11 | GSE233445 | GEO

Altered Ca+2 homeostasis induces Calpain-Cathepsin axis activation in sCJD.

Project description:Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrPSc). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca+2) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis. Here we describe the presence of massive regulation of Ca+2 responsive genes in sCJD brain tissue, accompanied by two Ca+2-dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Calpain 1 treatment enhances seeding activity of PrPSc in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons. Additionally, massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca+2 homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model. Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention.

2017-05-15 | GSE90977 | GEO

Preventing Site-specific Calpain Proteolysis of Junctophilin-2 Protects Against Stress-induced E-C Uncoupling and Heart Failure

Project description:Junctophilin-2 (JP2) is an essential component of the excitation-contraction coupling apparatus in cardiomyocytes and becomes proteolytically cleaved in response to stress. We previously mapped the primary calpain cleavage site to JP2 residues 565-566 using in vitro assays. To determine whether this site is responsible for JP2 cleavage in vivo, we generated calpain resistant JP2 (JP2CR) knock-in mice lacking this site. We find JP2 is not cleaved in JP2CR mice during pressure overload stress resulting in better cardiac outcomes and an attenuated transcriptional response relative to wildtype mice.

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Proteomic QSAR analysis of calpain substrate specificity

Project description:Calpains are intracellular Ca2+-regulated cysteine proteases that are essential for various cellular functions. Mammalian conventional calpains (calpain-1 and calpain-2) modulate the structure and function of their substrates by limited proteolysis; however, their substrate specificity remains unclear because the amino acid (aa) sequences around their cleavage sites are very diverse. To clarify calpains’ substrate specificities, 84 20-mer oligopeptides, corresponding to P10-P10’ of reported cleavage site sequences, were proteolyzed by calpains, and the catalytic efficiencies (kcat/Km) were globally determined by LC/MS. This analysis revealed 483 cleavage site sequences, including 360 novel ones. The kcat/Kms for 119 sites ranged from 12.5~1,710 M-1s-1. Most sites were cleaved by both calpain-1 and -2 with a similar kcat/Km. The aa compositions of the novel sites were not significantly different from the 420 previously reported sites, suggesting calpains have a strict implicit rule for sequence specificity, and that the limited proteolysis of intact substrates is due to the substrates’ higher-order structures. Cleavage position frequencies indicated that longer sequences N-terminal to the cleavage site (P-sites) than C-terminal (P’-sites) were preferred for proteolysis. Quantitative structure-activity relationship (QSAR) analyses using partial least-squares regression and >1,300 aa descriptors achieved kcat/Km prediction with r=0.834, and binary-QSAR modeling attained 64.8% prediction accuracy for 132 reported calpain cleavage sites independent of our model construction. These results outperformed previous calpain cleavage predictors, and revealed the importance of the P2, P3’, P4’, and P1-P2 contexts. This study increases our understanding of calpain substrate specificities, and opens calpains to “next-generation,” i.e., activity-related quantitative and context-dependent analyses.

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Preventing Site-specific Calpain Proteolysis of Junctophilin-2 Protects Against Stress-induced E-C Uncoupling and Heart Failure

Project description:Preventing Site-specific Calpain Proteolysis of Junctophilin-2 Protects Against Stress-induced E-C Uncoupling and Heart Failure

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MrgprD-expressing neurons maintain cutaneous mast cell homeostasis

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AR cooperates with SMAD4 to maintain muscle homeostasis

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GTPBP1 resolves paused ribosomes to maintain neuronal homeostasis

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DEK1 calpain overexpression

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2009-12-09 | E-GEOD-19268 | biostudies-arrayexpress

DEK1 calpain overexpression

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