Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1187288 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31372714.fastq.gz | Fastqsanger.gz | |||
| SRR31372714_1.fastq.gz | Fastqsanger.gz | |||
| SRR31372714_2.fastq.gz | Fastqsanger.gz | |||
| SRR31372715.fastq.gz | Fastqsanger.gz | |||
| SRR31372715_1.fastq.gz | Fastqsanger.gz |
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Project description:Cell death plasticity is crucial for modulating tissue homeostasis and immune responses, but our understanding of the molecular components that regulate cell death pathways to determine cell fate remains limited. Here, a CRISPR screen of acute myeloid leukemia cells identifies protein tyrosine phosphatase non-receptor type 23 (PTPN23) as essential for survival. Loss of PTPN23 activates nuclear factor-kappa B, apoptotic, necroptotic, and pyroptotic pathways by causing the accumulation of death receptors and toll-like receptors (TLRs) in endosomes. These effects are recapitulated by depletion of PTPN23 co-dependent genes in the endosomal sorting complex required for transport (ESCRT) pathway. Through proximity-dependent biotin labeling, we show that NAK-associated protein 1 interacts with PTPN23 to facilitate endosomal sorting of tumor necrosis factor receptor 1 (TNFR1), sensitizing cells to TNF-alpha-induced cytotoxicity. Our findings reveal PTPN23-dependent ESCRT machinery as a cell death checkpoint that regulates the spatiotemporal distribution of death receptors and TLRs to restrain multiple cell death pathways.
2024-10-16 | GSE272123 | GEO
Project description:PTPN23-dependent ESCRT machinery functions as a cell death checkpoint in restraining multiple cell death pathways
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Project description:In our study, a CRISPR screen of acute myeloid leukemia cells identifies protein tyrosine phosphatase non-receptor type 23 (PTPN23) as essential for survival. Loss of PTPN23 activates nuclear factor-kappa B, apoptotic, necroptotic, and pyroptotic pathways by causing the accumulation of death receptors and toll-like receptors (TLRs) in endosomes. These effects are recapitulated by depletion of PTPN23 co-dependent genes in the endosomal sorting complex required for transport (ESCRT) pathway. Through proximity-dependent biotin labeling, we show that NAK-associated protein 1 interacts with PTPN23 to facilitate endosomal sorting of tumor necrosis factor receptor 1 (TNFR1), sensitizing cells to TNF--induced cytotoxicity. Our findings reveal PTPN23-dependent ESCRT machinery as a cell death checkpoint that regulates the spatiotemporal distribution of death receptors and TLRs to restrain multiple cell death pathways.
2024-10-15 | PXD056836 |
Project description:We previously discovered WDR4 as a Cullin 4 ubiquitin ligase substrate adaptor, which associates with poor cancer prognosis. With the help of ubiquitylome analysis, we uncovered PTPN23 as a substrate of WDR4. While PTPN23 is a component of ESCRT complex that facilitates EGFR lysosomal trafficking and degradation, the high expression of WDR4 and low expression of PTPN23 in patient sample suggesting that WDR4-mediated PTPN23 ubiquitination might contribute to PTPN23 proteasomal degradation and lead to poor patient survival rate. To prevent PTPN23 from WDR4-mediated ubiquitination, we used fine mapping to figure out the binding site of these two proteins and identified a 40-amino acid region on PTPN23 (Bro1 domain) can bind with WDR4, we named this 40-amino acid region as Bro40. Structural docking of WDR4 and Bro1 showed that the N-term of Bro40 is the favorable contact site. Thus, 6 amino acids at the N-term of Bro40 were mutated into alanine, so called Bro40mut. Bro40 and Bro40mut were fused on a GFP-tag plasmid for functional test and animal experiment. The tumor suppressing function of Bro40 was confirm by migration/invasion assays and animal model. To understand how Bro40 regulates cancer progression at RNA level, we transfected Bro40 and Bro40mut into H1299 cells followed by RNA sequencing.
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Project description:Exosomes play pleiotropic tumor-promoting functions and are originated from a diversion of endocytic pathway. In late endocytic trafficking, multivesicular bodies (MVBs) are directed to lysosomes for degradation or secreted as exosomes. However, the mechanism controlling different fates of MVBs remains elusive. Here, we show that WDR4 promotes exosome secretion through the degradation of PTPN23, an ESCRT-associated Bro1-family protein. Mechanistically, PTPN23 competes with ALIX, another Bro1-family protein, for binding syntenin, thus enabling PTPN23 and ALIX for promoting MVBs towards degradation and secretion, respectively. Furthermore, ALIX uniquely recruits actin-capping/severing proteins to prevent F-actin accumulation around MVBs, thereby facilitating MVBs trafficking to cell periphery for secretion. Functionally, the WDR4/ALIX-dependent exosomes preferentially load pro-tumor proteins including PTK2, MCAM and NRP1, thereby enhancing metastasis and immune evasion. This study highlights a previously unprecedented mechanism for regulating MVBs fates and exosome cargos, which have potential broad impacts on tuning exosome production and devising cancer therapeutic strategy.
2025-01-24 | PXD050029 | Pride
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.
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Project description:Signalling by target-derived neurotrophins is essential for the correct development of the nervous system and its maintenance throughout life. Several aspects concerning the lifecycle of neurotrophins and their receptors, tropomyosin receptor kinases (Trks) and p75NTR, have been characterised over the years, including formation of activated ligand-receptor complexes, their endocytosis, trafficking and signalling. However, the molecular mechanisms directing the sorting of activated neurotrophin receptors to their final cellular destination are not completely understood. Previously, our laboratory identified Bicaudal-D1 (BICD1), a dynein motor adaptor, as a key factor for lysosomal degradation of BDNF-activated TrkB and p75NTR in motor neurons. Here, we deciphered the mechanism responsible for this sorting process. Using a proteomic approach, we identified protein tyrosine phosphatase, non-receptor type 23 (PTPN23), a member of the endosomal sorting complexes required for transport (ESCRT) machinery, in the BICD1 interactome. Molecular mapping revealed that PTPN23 is not a canonical BICD1 cargo; instead, PTPN23 binds the N-terminus of BICD1, which is also essential for the recruitment of cytoplasmic dynein. In line with the BICD1 knockdown phenotype, loss of PTPN23 leads to increased accumulation of BDNF-activated p75NTR and TrkB in swollen vacuole-like compartments, suggesting that neuronal PTPN23 is a novel regulator of the endocytic sorting of neurotrophin receptors.
2020-05-26 | PXD016190 | Pride
Project description:Components of the ESCRT machinery act downstream of MLKL to regulate necroptotic cell death and its consequences
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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
Project description:Aberrant overexpression or activation of EGFR drives the development of non-small cell lung cancer (NSCLC) and acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) by secondary EGFR mutations or c-MET amplification/activation remains as a major hurdle for NSCLC treatment. We previously identified WDR4 as a substrate adaptor of Cullin 4 ubiquitin ligase and an association of WDR4 high expression with poor prognosis of lung cancer. Here, using an unbiased ubiquitylome analysis, we uncover PTPN23, a component of the ESCRT complex, as a substrate of WDR4- based ubiquitin ligase. WDR4-mediated PTPN23 ubiquitination leads to its proteasomal degradation, thereby suppressing lysosome trafficking and degradation of wild type EGFR, EGFR mutant, and c-MET. Through this mechanism, WDR4 sustains EGFR and c-MET signaling to promote NSCLC proliferation, migration, invasion, stemness, and metastasis. Clinically, PTPN23 is downregulated in lung cancer and its low expression correlates with WDR4 high expression and poor prognosis. Targeting WDR4-mediated PTPN23 ubiquitination by a peptide that competes with PTPN23 for binding WDR4 promotes EGFR and c-MET degradation to block the growth and progression of EGFR TKI-resistant NSCLC. These findings identify a central role of WDR4/PTPN23 axis in EGFR and c-MET trafficking and a potential therapeutic target for treating EGFR TKI-resistant NSCLC.
2023-10-09 | PXD025361 | Pride