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Manipulating the lysine-arginine balance for successful therapy of malignant glioma by targeting lysosomal membrane integrity [III]

ABSTRACT: Manipulating the lysine-arginine balance for successful therapy of malignant glioma by targeting lysosomal membrane integrity [III]

PROVIDER: PRJNA1002308 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25525995_1.fastq.gz	Fastqsanger.gz
	SRR25525995_2.fastq.gz	Fastqsanger.gz
	SRR25525996_1.fastq.gz	Fastqsanger.gz
	SRR25525996_2.fastq.gz	Fastqsanger.gz

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Manipulating the lysine-arginine balance for successful therapy of malignant glioma by targeting lysosomal membrane integrity [I]

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Manipulating the lysine-arginine balance for successful therapy of malignant glioma by targeting lysosomal membrane integrity [II]

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Project description:Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic and degenerative disease in humans. Here, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B downregulated mTOR activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via the transcription factor TFEB, which increased lysosomal biogenesis and activation of autophagy-initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome population and basic recycling functions in the cell. We used microarrays to explore the gene expression profiles differentially expressed in bone marrow-derived macrophages (BMDM) isolated from cathepsin B-/- and wild-type mice.

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