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PTPN23 downregulation by WDR4 Determines the Exosome Secretion Fate of MVB to Promote Cancer Metastasis and Immune Evasion

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung, Permanent Cell Line Cell

DISEASE(S): Non-small Cell Lung Carcinoma

SUBMITTER: Nai-Yang Yeat

LAB HEAD: Ruey-Hwa Chen

PROVIDER: PXD050029 | Pride | 2025-01-24

REPOSITORIES: pride

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			Action	DRS
	checksum.txt	Txt
	exo_C-1.raw	Raw
	exo_C-2.raw	Raw
	exo_C-3.raw	Raw
	exo_W4-1.raw	Raw

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PTPN23 ubiquitination by WDR4 suppresses EGFR and c-MET degradation to define a lung cancer therapeutic target

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

The fission yeast MTREC complex targets CUTs and unspliced mRNAs to the nuclear exosome [RNA-Seq]

Project description:Cryptic unstable transcripts (CUTs) are rapidly degraded by the nuclear exosome, however, the way they are recognized and targeted to the exosome is not fully understood. The recently identified Schizosaccharomyces pombe MTREC complex has been shown to promote degradation of meiotic mRNAs and regulatory ncRNAs. Here, we report that the MTREC complex is also the major nuclear exosome targeting complex for CUTs and unspliced mRNAs. MTREC complex specifically binds to CUTs, meiotic mRNAs and unspliced mRNA transcripts and targets these RNAs for degradation by the nuclear exosome, while the TRAMP complex has only a minor role in this process. The MTREC complex physically interacts with the nuclear exosome and with various RNA-binding and -processing complexes, coupling RNA processing to the RNA degradation machinery. Our study reveals the central role of the evolutionarily conserved MTREC complex in RNA quality control, and in the recognition and elimination of aberrant, cryptic transcripts. RNA sequencing of WT and mutant S.pombe strains, processed data is normalized to median non-intron containing gene-expression, no replicates

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Effect of Bro40 and Bro40mut on gene expression of wild type H1299 non-small cell lung cancer cell line

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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Altered Biogenesis and MicroRNA Content of Hippocampal Exosomes Following Experimental Status Epilepticus

Project description:Here, we characterised the effects of experimental status epilepticus on the expression of exosome biosynthesis components and analysed microRNA content in exosome-enriched fractions prepared from the mouse hippocampus. Status epilepticus induced by unilateral intra-amygdala kainic acid resulted in acute subfield-specific, bi-directional changes in transcripts associated with exosome biosynthesis including up-regulation of ESCRT–dependent and –independent pathways. Increased expression of exosome components including Alix were detectable in samples obtained two weeks after status epilepticus and changes occurred in both the ipsilateral and contralateral hippocampus. Small RNAseq analysis of exosome-enriched fractions prepared using two different techniques detected a rich diversity of conserved microRNAs and determined status epilepticus selectively alters microRNA contents, including upregulation of the glia-enriched miR-21a-3p. We also characterized editing sites of the exosome-enriched miRNAs and found six exosome-enriched miRNAs that were Adenosine-to-Inosine (ADAR) edited with the majority of the editing events predicted to occur within miRNA seed regions. However, the prevalence of these editing events was not altered by status epilepticus. These studies demonstrate status epilepticus alters the exosome pathway and its microRNA content, but not editing patterns.

2019-12-12 | GSE136695 | GEO

PTPN23-dependent ESCRT machinery functions as a cell death checkpoint in restraining multiple cell death pathways

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.

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Distinct functions of dimeric and monomeric Alix in regulating F-actin assembly and loading of exosomal cargo

Project description:Alix is a ubiquitously expressed scaffold protein that participates in numerous cellular processes, relating to the remodeling/repair of membranes and the actin cytoskeleton. Alix exists in monomeric and dimeric/multimeric configurations, but how dimer formation occurs and what role the dimer has in Alix-mediated processes are questions still largely elusive. Here, we reveal a mechanism for Alix homodimerization mediated by disulfide bonds under physiological conditions and demonstrate that Alix dimer is enriched in exosome and F-actin cytoskeleton subcellular fractions. Proteomic analysis of exosomes derived from Alix−/− primary cells underlined Alix indispensable role in loading syntenin into exosomes, thereby regulating the cellular levels of this protein. Using a set of Alix deletion mutants, we could define the function of the Bro1 domain, which is solely required for Alix’ exosomal localization, and that of the V domain, which is needed for recruiting syntenin into exosomes. We reveal an essential role for Cys814 within the disordered proline rich domain (PRD) for Alix dimerization. By mutating this residue, Alix remains exclusively monomeric and, in this configuration, is more effective in loading syntenin into exosomes. In contrast, loss of dimerization affects Alix ability to associate with F-actin, thereby compromising Alix-mediated cytoskeleton remodeling. We propose that by 3 shifting the ratio between its dimeric and monomeric forms, Alix selectively executes two of its main functions, exosomal cargo loading or cytoskeleton remodeling.

2022-10-14 | PXD031450 | Pride

ECM deposition is driven by caveolin1-dependent regulation of exosomal biogenesis and cargo sorting

Project description:The composition and physical properties of the extracellular matrix (ECM) critically influence tumor progression, but the molecular mechanisms underlying ECM layering are poorly understood. Tumor-stroma interaction is critically dependent on cell-cell communication mediated by exosomes, small vesicles generated within multivesicular bodies (MVBs). Here, we show that caveolin-1 (Cav1) is a central modulator of both exosome biogenesis and exosomal protein cargo sorting through the regulation of cholesterol content at the endosomal compartment/MVBs. Quantitative proteomics profiling revealed that Cav1 is required for exosomal sorting of ECM protein cargo subsets including tenascin-C (TnC), and for fibroblast-derived exosomes to efficiently depose ECM and promote tumor cell invasiveness. Cav1-driven exosomal ECM deposition not only promotes local stromal remodeling, but also the generation of distant ECM-enriched stromal niches. These results support a model by which Cav1 is a central regulatory hub for tumor-stroma interactions through a novel exosome-dependent ECM deposition mechanism. Linked studies: <a href='https://www.ebi.ac.uk/metabolights/MTBLS1977' rel='noopener noreferrer' target='_blank'>MTBLS1977</a>

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ECM deposition is driven by caveolin1-dependent regulation of exosomal biogenesis and cargo sorting

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2021-03-03 | PXD024031 | Pride

Controlled release of exosomes by AMPK/SREBPs pathway

Project description:Exosome-like extracellular vesicles (EVs) are very important vesicles for intercellular signal transmission. Although host factors involving exosome-like EV production and release has been reported, the cellular signaling pathway regulating EV production is largely unknown. Here we performed a kinase inhibitor library screening to identify pathways controlling EV’s production. We found a kinase inhibitor, APY0201, which significantly increased EV secretion through upregulation of intracellular sterol synthesis and the volume of intracellular multivesicular bodies (MVBs). APY0201 specifically caused the decrease of AMP-activated protein kinase (AMPK) phosphorylation and activation of sterol regulatory element-binding protein (SREBP1), a pivotal transcription factor of sterol synthesis gene expression. In addition, both AMPK agonist and SREBP inhibitor deteriorate augmented EV production induced by APY0201. Ectopic expression of AMPK and SREBP1 corroborated that AMPK and SREBP1 are two major host factors governing the production of exosome-like EVs. Taken together, we identified that APY0201 is a novel kinase inhibitor targeting AMPK-SREBP1 pathway which is important for EV biogenesis and release. Our findings might pave the way to achievable finely upregulated EV production.

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