USP17 is required for peripheral trafficking of lysosomes

Lin, J.; McCann, Aidan; Sereesongsaeng, Naphannop; Burden, Jonathan M; Alsa'd, Alhareth A; Burden, Roberta E.; Micu, Ileana; Williams, Richard V.; Schaeybroeck, Sandra Van; Evergren, Emma; Mullan, Paul B.; Simpson, Jeremy C.; Scott, Christopher J.; Burrows, James F.

doi:10.15252/embr.202051932

Cited by 10 publications

(5 citation statements)

References 36 publications

(74 reference statements)

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“…We identified TSS hypermethylation (suggesting gene downregulation) of genes from the family of USP17, a deubiquitinating enzyme that has been implicated in several cellular functions, such as cell cycle progression, 58 chemokine-driven cell motility, endocytosis, and peripheral lysosome trafficking. 59 This enzyme has not been previously associated with FTD; however, ubiquitindependent signaling is a well-known disease-related process Cumulative scores for hypermethylated DMRs of the presymptomatic group were significantly higher in presymptomatic carriers than in healthy controls (A) and symptomatic carriers (C). Conversely, cumulative scores for hypermethylated DMRs of the healthy control group (B) and of the symptomatic group (D) were significantly higher in these groups than in presymptomatic carriers.…”

Section: Discussionmentioning

confidence: 90%

“…We identified TSS hypermethylation (suggesting gene downregulation) of genes from the family of USP17, a deubiquitinating enzyme that has been implicated in several cellular functions, such as cell cycle progression, 58 chemokine‐driven cell motility, endocytosis, and peripheral lysosome trafficking 59 . This enzyme has not been previously associated with FTD; however, ubiquitin‐dependent signaling is a well‐known disease‐related process in several neurodegenerative disorders, contributing to protein degradation, regulation of neuronal function, and inflammation 60 .…”

Section: Discussionmentioning

confidence: 99%

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Distinctive cell‐free DNA methylation characterizes presymptomatic genetic frontotemporal dementia

Giannini,

Boers,

van der Ende

et al. 2024

Ann Clin Transl Neurol

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ObjectiveMethylation of plasma cell‐free DNA (cfDNA) has potential as a marker of brain damage in neurodegenerative diseases such as frontotemporal dementia (FTD). Here, we study methylation of cfDNA in presymptomatic and symptomatic carriers of genetic FTD pathogenic variants, next to healthy controls.MethodscfDNA was isolated from cross‐sectional plasma of 10 presymptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), 10 symptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), and 9 healthy controls. Genome‐wide methylation of cfDNA was determined using a high‐resolution sequencing technique (MeD‐seq). Cumulative scores based on the identified differentially methylated regions (DMRs) were estimated for presymptomatic carriers (vs. controls and symptomatic carriers), and reevaluated in a validation cohort (8 presymptomatic: 3 C9orf72, 3 GRN, and 2 MAPT; 26 symptomatic: 7 C9orf72, 6 GRN, 12 MAPT, and 1 TARDBP; 13 noncarriers from genetic FTD families).ResultsPresymptomatic carriers showed a distinctive methylation profile compared to healthy controls and symptomatic carriers. Cumulative DMR scores in presymptomatic carriers enabled to significantly differentiate presymptomatic carriers from healthy controls (p < 0.001) and symptomatic carriers (p < 0.001). In the validation cohort, these scores differentiated presymptomatic carriers from symptomatic carriers (p ≤ 0.007) only. Transcription‐start‐site methylation in presymptomatic carriers, generally associated with gene downregulation, was enriched for genes involved in ubiquitin‐dependent processes, while gene body methylation, generally associated with gene upregulation, was enriched for genes involved in neuronal cell processes.InterpretationA distinctive methylation profile of cfDNA characterizes the presymptomatic stage of genetic FTD, and could reflect neuronal death in this stage.

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Section: Discussionmentioning

confidence: 90%

“…We identified TSS hypermethylation (suggesting gene downregulation) of genes from the family of USP17, a deubiquitinating enzyme that has been implicated in several cellular functions, such as cell cycle progression, 58 chemokine‐driven cell motility, endocytosis, and peripheral lysosome trafficking 59 . This enzyme has not been previously associated with FTD; however, ubiquitin‐dependent signaling is a well‐known disease‐related process in several neurodegenerative disorders, contributing to protein degradation, regulation of neuronal function, and inflammation 60 .…”

Section: Discussionmentioning

confidence: 99%

Distinctive cell‐free DNA methylation characterizes presymptomatic genetic frontotemporal dementia

Giannini,

Boers,

van der Ende

et al. 2024

Ann Clin Transl Neurol

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“…Therefore, further studies are needed to shed light on the molecular mechanisms of regulation. Intriguingly, in addition to PtdIns3P, the ubiquitin system has been shown to regulate lysosome positioning, particularly the ER-embedded UBE2J1/RNF26 ubiquitylation complex and the opposing deubiquitinating enzyme USP15 51 , 52 , the ubiquitin domain-containing protein 1 (UBTD1) 53 and deubiquitinase USP17 54 . Further investigations will reveal whether these represent an alternative pathway or whether ubiquitylation cross talks with phosphoinositide regulation.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor EB regulates phosphatidylinositol-3-phosphate levels that control lysosome positioning in the bladder cancer model

et al. 2023

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Lysosomes orchestrate degradation and recycling of exogenous and endogenous material thus controlling cellular homeostasis. Little is known how this organelle changes during cancer. Here we investigate the intracellular landscape of lysosomes in a cellular model of bladder cancer. Employing standardized cell culture on micropatterns we identify a phenotype of peripheral lysosome positioning prevailing in bladder cancer cell lines but not normal urothelium. We show that lysosome positioning is controlled by phosphatidylinositol-3-phosphate (PtdIns3P) levels on endomembranes which recruit FYVE-domain containing proteins for lysosomal dispersion. We identify transcription factor EB (TFEB) as an upstream regulator of PtdIns3P production by VPS34 that is activated in aggressive bladder cancer cells with peripheral lysosomes. This conceptually clarifies the dual role of TFEB as regulator of endosomal maturation and autophagy, two distinct processes controlled by PtdIns3P. Altogether, our findings uncover peripheral lysosome positioning, resulting from PtdIns3P production downstream of TFEB activation, as a potential biomarker for bladder cancer.

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“…Moreover, an oncogenic EGF expression stimulates peripheral trafficking of lysosome, which is regulated by the deubiquitinase, USP17. USP17 induces the secretion of cathepsin D and promotes plasma membrane repair [ 253 ]. Since lysosome-mediated plasma membrane repair is dependent on Ca 2+ influx, shedding of lysosome-derived ectosomes can probably occur under other conditions where intracellular Ca 2+ levels are elevated.…”

Section: Lysosomal Involvement In Cancermentioning

confidence: 99%

Lysosomes in Cancer—At the Crossroad of Good and Evil

Eriksson,

Öllinger

2024

Cells

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Although it has been known for decades that lysosomes are central for degradation and recycling in the cell, their pivotal role as nutrient sensing signaling hubs has recently become of central interest. Since lysosomes are highly dynamic and in constant change regarding content and intracellular position, fusion/fission events allow communication between organelles in the cell, as well as cell-to-cell communication via exocytosis of lysosomal content and release of extracellular vesicles. Lysosomes also mediate different forms of regulated cell death by permeabilization of the lysosomal membrane and release of their content to the cytosol. In cancer cells, lysosomal biogenesis and autophagy are increased to support the increased metabolism and allow growth even under nutrient- and oxygen-poor conditions. Tumor cells also induce exocytosis of lysosomal content to the extracellular space to promote invasion and metastasis. However, due to the enhanced lysosomal function, cancer cells are often more susceptible to lysosomal membrane permeabilization, providing an alternative strategy to induce cell death. This review summarizes the current knowledge of cancer-associated alterations in lysosomal structure and function and illustrates how lysosomal exocytosis and release of extracellular vesicles affect disease progression. We focus on functional differences depending on lysosomal localization and the regulation of intracellular transport, and lastly provide insight how new therapeutic strategies can exploit the power of the lysosome and improve cancer treatment.

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USP17 is required for peripheral trafficking of lysosomes

Cited by 10 publications

References 36 publications

Distinctive cell‐free DNA methylation characterizes presymptomatic genetic frontotemporal dementia

Distinctive cell‐free DNA methylation characterizes presymptomatic genetic frontotemporal dementia

Transcription factor EB regulates phosphatidylinositol-3-phosphate levels that control lysosome positioning in the bladder cancer model

Lysosomes in Cancer—At the Crossroad of Good and Evil

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