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USP8 coordinates ESCRT-mediated membrane repair, xenophagy, and oxidative stress responses during Mycobacterium tuberculosis infection

ABSTRACT: We show that USP8 colocalizes with intracellular Mtb, recognizes phagosomal membrane damage, and is required for ESCRT-dependent membrane repair. Furthermore, USP8 regulates the NRF2-dependent antioxidant signature. Taken together, our study shows a central role of USP8 in promoting intracellular growth of Mtb by coordinating phagosomal membrane repair, ubiquitin-driven selective autophagy, and the oxidative stress response.

ORGANISM(S): Mus musculus

PROVIDER: GSE240372 | GEO | 2024/08/07

REPOSITORIES: GEO

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USP8 coordinates ESCRT-mediated membrane repair, xenophagy, and oxidative stress responses during Mycobacterium tuberculosis infection

Project description:USP8 coordinates ESCRT-mediated membrane repair, xenophagy, and oxidative stress responses during Mycobacterium tuberculosis infection

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Systematic analysis of ESCRT mutants reveals an essential function for the MVB pathway in amino acid recycling.

Project description:The ESCRT machinery drives the multivesicular body (MVB) pathway in eukaryotic cells and thus is required for the degradation of ubiquitinated membrane proteins in lysosomes. To systematically characterize how cells respond to loss of ESCRT function, we used quantitative proteomics and gene expression profiling in yeast. We find that ESCRT mutants display severe defects in amino acid homeostasis, resulting in lower levels of free intracellular amino acids. This deficit renders the growth of ESCRT mutants highly sensitive to nutrient limitation. Further proteomic analysis revealed that the MVB pathway essentially contributes to proteome remodeling under nutrient limitation. The rapid decline of protein synthesis upon starvation no longer enables ESCRT mutants to complete their cell cycle and properly enter a quiescent state, which strongly affects their long-term survival. Thus, the MVB pathway functions to selectively down-regulate integral membrane proteins and, together with autophagy and proteasomal degradation, considerably contributes to amino acid recycling. We used microarrays to identify gene expression changes between delta VPS4 knock out and wild type Saccharomyces cerevisiae strains

2018-01-01 | GSE53774 | GEO

ESCRT-I controls lysosomal membrane protein homeostasis and restricts MCOLN1-dependent TFEB/TFE3 signaling.

Project description:Within the endolysosomal pathway in mammalian cells, ESCRT complexes facilitate degradation of membrane proteins from limiting membranes of late endosomes. Recent studies revealed that yeast ESCRT proteins also sort for degradation, ubiquitinated proteins from vacuolar membrane. However, whether mammalian ESCRTs perform similar function at lysosomes remained unknown. Here, we studied the involvement of mammalian ESCRT-I in maintaining lysosomal membrane homeostasis and its implication in lysosome-related signaling. We show that ESCRT-I restricts the size of lysosomes and promotes degradation of lysosomal Ca2+ channel, MCOLN1 protein. ESCRT-I depletion induced transcriptional response related to MiT-TFE signaling and cholesterol biosynthesis, pointing to lysosomal dysfunction. The lack of ESCRT-I promoted abnormal cholesterol accumulation on lysosomes and activated TFEB/TFE3 transcription factors in Ca2+-MCOLN1-dependent, but lipid-independent manner. Hence, our study provides evidence that ESCRT-I maintains lysosomal homeostasis and elucidates MiT-TFE regulatory mechanism activated in response to ESCRT-I deprivation

2022-03-28 | GSE178665 | GEO

Transcriptome profiling of wild-type (WT) and USP8 knockout (KO) CT26 cell lines

Project description:USP8 is one of DUBs and is frequently overexpressed or gain-of-function mutated in multiple types of human cancer. Importantly, USP8 has been identified as an immunomodulatory DUB as T cell-specific Usp8 deficiency disrupts regulatory T cell functions, leading to recruiting abundant CD8+ T cells in colons and resulting in the inflammatory bowel disease in mice. However, whether targeting USP8 can enhance anti-tumor immunity has not been reported. To further explore the physiological function of USP8, we performed the transcriptomic analysis to comprehensively understand which signaling pathways are mainly regulated by USP8 in cancer cells. Usp8 WT and KO CT26 cells were harvested for RNA-sequencing (RNA-seq).

2022-02-14 | GSE164558 | GEO

Components of the ESCRT machinery act downstream of MLKL to regulate necroptotic cell death and its consequences

Project description:The activation of Mixed Lineage Kinase-Like (MLKL) by Receptor Interacting Protein Kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated necrosis, called necroptosis. Here we show that during necroptosis, MLKL-dependent calcium (Ca++) influx and phosphatidylserine (PS) exposure on the outer leaflet of the plasma membrane preceded loss of PM integrity. Activation of MLKL results in the generation of broken, PM “bubbles” with exposed PS that are released from the surface of the otherwise intact cell. Components of the ESCRT machinery are required for formation of these bubbles, and act to sustain survival of the cell when MLKL activation is limited or reversed. Under conditions of necroptotic cell death, ESCRT controls the duration of plasma membrane integrity. As a consequence of the action of ESCRT, cells undergoing necroptosis can express chemokines and other regulatory molecules, and promote antigenic cross-priming of CD8+ T cells.

2017-06-16 | GSE85660 | GEO

Differential microRNA Expression in USP8-Mutated and Wild-Type Corticotroph Pituitary Tumors Reflect the Difference in Protein Ubiquitination Processes

Project description:Background: USP8 mutations are the most common driver changes in corticotroph pituitary tumors. They have direct effect on cells’ proteome through disturbance of ubiquitination process and also influence gene expression. The aim of this study was to compare microRNA profiles in USP8- mutated and wild-type tumors and determine the probable role of differential microRNA expression by integrative microRNA and mRNA analysis. Methods: Patients with Cushing’s disease (n = 28) and silent corticotroph tumors (n = 20) were included. USP8 mutations were identified with Sanger sequencing. MicroRNA and gene expression was determined with next-generation sequencing. Results: USP8-mutated patients with Cushing’s disease showed higher rate of clinical remission and trend towards lower tumor volume than wild-type patients. Comparison of microRNA profiles of USP8-mutated and wild-type tumors revealed 68 differentially expressed microRNAs. Their target genes were determined by in silico prediction and microRNA/mRNA correlation analysis. GeneSet Enrichment analysis of putative targets showed that the most significantly overrepresented genes are involved in protein ubiquitination-related processes. Only few microRNAs influence the expression of genes differentially expressed between USP8-mutated and wild-type tumors. Conclusions: Differences in microRNA expression in corticotropinomas stratified according to USP8 status reflect disturbed ubiquitination processes, but do not correspond to differences in gene expression between these tumors.

2021-02-06 | GSE166279 | GEO

ATG9A is a component of the ESCRT system and governs plasma membrane repair

Project description:ATG9 is often described as the sole transmembrane protein among the core autophagy factors. The mammalian ATG9A is notorious for trafficking through numerous cellular compartments including the plasma membrane. The reasons for ATG9As wide intracellular distribution and its role at the PM are not fully understood. Here we show that ATG9A intimately interacts with components of the ESCRT system. Employing proteomic analyses with APEX2-ATG9A we identified a number of ESCRTs as ATG9A interactors, including TSG101 and ALIX, and uncovered cooperation between ATG9A and ESCRTs in protection against PM damage. ATG9A knockouts sensitized PM to permeabilization by a broad spectrum of agents including gasdermin and Mycobacterium tuberculosis. ESCRTs phenocopied ATG9A in protection against PM injury. Thus, in addition to its function in autophagy, ATG9A is a component of the ESCRT system engaged in the repair of PM

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Project description:The analysis to identify ubiquitinated proteins increased on endosomes in USP8-depleted cells.

2023-12-17 | PXD042488 | Pride

Trancriptome analysis of tumor tissue to search for the associations between USP8 mutation status, molecular markers of pituitary adenomas, and clinical, and diagnostic parametres of Cushing disease

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TMT 6-plex proteome analyisis of USP8-depleted cells

Project description:The analysis to investigate the change in proteome of USP8-depleted cells

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