Concurrent depletion of Vps37 proteins evokes ESCRT-I destabilization and profound cellular stress responses

Kolmus, Krzysztof; Erdenebat, Purevsuren; Szymańska, Ewelina; Stewig, Blair; Goryca, Krzysztof; Derezińska-Wołek, Edyta; Szumera‐Ciećkiewicz, Anna; Brewińska-Olchowik, Marta; Piwocka, Katarzyna; Prochorec‐Sobieszek, Monika; Mikula, Michał; Miączyńska, Marta

doi:10.1242/jcs.250951

Cited by 17 publications

(16 citation statements)

References 98 publications

(140 reference statements)

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“…Hence, in addition to the previously reported induction of inflammatory signaling (Maminska et al, 2016;Kolmus et al, 2021), ESCRT-I depletion activates transcriptional responses suggestive of lysosomal stress or impaired delivery of nutrients from autolysosomal and endolysosomal compartments.…”

Section: Escrt-i Deficiency Activates Transcription Of Genes Involved...mentioning

confidence: 77%

“…Using an siRNA-mediated approach, we efficiently depleted key ESCRT-I subunits, Tsg101 or Vps28, in RKO cells (Fig S1A). Of note, the removal of one of them strongly reduced the levels of the other because of the ESCRT-I complex destabilization, as described (Bache et al, 2004;Kolmus et al, 2021). First, we analyzed by confocal microscopy whether knockdown of Tsg101 or Vps28 in RKO cells affected the intracellular distribution of LAMP1, a marker of late endosomes and lysosomes (Fig S1B).…”

Section: Escrt-i Deficiency Leads To Appearance Of Enlarged Structure...mentioning

confidence: 86%

“…Lysosomes have recently emerged as important players in cancer development or progression, and targeting their function has been proposed as a promising strategy in cancer treatment (Tang et al, 2020;Machado et al, 2021). Recently, we showed that components of the ESCRT machinery could serve as potential therapeutic targets (Szymanska et al, 2020;Kolmus et al, 2021), but whether modulation of ESCRT activity would affect lysosomal function in CRC cells has not been tested. Here, by a comprehensive analysis of the morphology and function of lysosomes in CRC cells, we discover that mammalian ESCRT-I proteins, Tsg101 or Vps28, control lysosomal size and homeostasis, regulating lysosomal membrane protein turnover and endolysosomal transport of cholesterol.…”

Section: Discussionmentioning

confidence: 99%

“…To address whether ESCRT-I is involved in lysosomal membrane homeostasis and signaling, we used CRC cells, in which we previously reported ESCRT-I to regulate cell growth and intracellular signaling (Kolmus et al, 2021). Using an siRNA-mediated approach, we efficiently depleted key ESCRT-I subunits, Tsg101 or Vps28, in RKO cells (Fig S1A).…”

Section: Escrt-i Deficiency Leads To Appearance Of Enlarged Structure...mentioning

confidence: 99%

“…With the exception of one very recent report showing that some ESCRT-III components and Vps4 mediate degradation of several lysosomal membrane proteins (Zhang et al, 2021), the role of ESCRTs in the physiological regulation of lysosomal morphology, function, or signaling in the absence of induced lysosomal damage has not been thoroughly addressed. This question is important for human health as lysosomal function and signaling contribute to development or progression of cancer (Tang et al, 2020;Machado et al, 2021), including colorectal cancer (CRC), in which ESCRT machinery has been proposed as a promising therapeutic target (Szymanska et al, 2020;Kolmus et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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ESCRT-I fuels lysosomal degradation to restrict TFEB/TFE3 signaling via the Rag-mTORC1 pathway

et al. 2022

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Within the endolysosomal pathway in mammalian cells, ESCRT complexes facilitate degradation of proteins residing in endosomal membranes. Here, we show that mammalian ESCRT-I restricts the size of lysosomes and promotes degradation of proteins from lysosomal membranes, including MCOLN1, a Ca2+ channel protein. The altered lysosome morphology upon ESCRT-I depletion coincided with elevated expression of genes annotated to biogenesis of lysosomes due to prolonged activation of TFEB/TFE3 transcription factors. Lack of ESCRT-I also induced transcription of cholesterol biosynthesis genes, in response to inefficient delivery of cholesterol from endolysosomal compartments. Among factors that could possibly activate TFEB/TFE3 signaling upon ESCRT-I deficiency, we excluded lysosomal cholesterol accumulation and Ca2+-mediated dephosphorylation of TFEB/TFE3. However, we discovered that this activation occurs due to the inhibition of Rag GTPase–dependent mTORC1 pathway that specifically reduced phosphorylation of TFEB at S112. Constitutive activation of the Rag GTPase complex in cells lacking ESCRT-I restored S112 phosphorylation and prevented TFEB/TFE3 activation. Our results indicate that ESCRT-I deficiency evokes a homeostatic response to counteract lysosomal nutrient starvation, that is, improper supply of nutrients derived from lysosomal degradation.

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Section: Escrt-i Deficiency Activates Transcription Of Genes Involved...mentioning

confidence: 77%

Section: Escrt-i Deficiency Leads To Appearance Of Enlarged Structure...mentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Escrt-i Deficiency Leads To Appearance Of Enlarged Structure...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ESCRT-I fuels lysosomal degradation to restrict TFEB/TFE3 signaling via the Rag-mTORC1 pathway

et al. 2022

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VPS72, a member of VPS protein family, can be used as a new prognostic marker for hepatocellular carcinoma

Huang

Jin

Wang

et al. 2023

Immunity Inflam & Disease

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Background Vacuolar protein sorting (VPS) plays a crucial role in intracellular molecular transport between organelles. However, studies have indicated a correlation between VPSs and tumorigenesis and the development of several cancers. Nevertheless, the association between VPSs and hepatocellular carcinoma (HCC) remains unclear. Methods By analyzing databases such as The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC), we investigated the differences in VPSs expression between normal tissue and HCC transcriptomes. Furthermore, we examined the relationship between VPSs expression and overall survival (OS) in patients with HCC. Univariate and multivariate Cox analyses were employed to assess the prognostic value of VPS72 as an independent factor, and the correlation between VPS72 and the tumor immune microenvironment was also analyzed. Results We observed significant overexpression of 28 VPSs in HCC tissues compared to normal tissues. The mRNA expression of VPSs displayed a negative correlation with OS, while exhibiting a positive correlation with tumor grade and stage. Additionally, both univariate and multivariate Cox analyses identified VPS72 as a potential independent risk factor for HCC prognosis. Overexpression of VPS72 demonstrated a positive correlation with various clinicopathological factors associated with poor prognosis, as well as the infiltration levels of immune cells. Conclusion Therefore, our research shows that VPSs participate in HCC occurrence and development, especially VPS72, which may act as a potential target for HCC treatment and prognosis biomarker.

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NFκB and JNK pathways mediate metabolic adaptation upon ESCRT-I deficiency

Cendrowski,

Wrobel,

Mazur

et al. 2024

Cell. Mol. Life Sci.

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Endosomal Sorting Complexes Required for Transport (ESCRTs) are crucial for delivering membrane receptors or intracellular organelles for lysosomal degradation which provides the cell with lysosome-derived nutrients. Yet, how ESCRT dysfunction affects cell metabolism remained elusive. To address this, we analyzed transcriptomes of cells lacking TSG101 or VPS28 proteins, components of ESCRT-I subcomplex. ESCRT-I deficiency reduced the expression of genes encoding enzymes involved in oxidation of fatty acids and amino acids, such as branched-chain amino acids, and increased the expression of genes encoding glycolytic enzymes. The changes in metabolic gene expression were associated with Warburg effect-like metabolic reprogramming that included intracellular accumulation of lipids, increased glucose/glutamine consumption and lactate production. Moreover, depletion of ESCRT-I components led to expansion of the ER and accumulation of small mitochondria, most of which retained proper potential and performed ATP-linked respiration. Mechanistically, the observed transcriptional reprogramming towards glycolysis in the absence of ESCRT-I occurred due to activation of the canonical NFκB and JNK signaling pathways and at least in part by perturbed lysosomal degradation. We propose that by activating the stress signaling pathways ESCRT-I deficiency leads to preferential usage of extracellular nutrients, like glucose and glutamine, for energy production instead of lysosome-derived nutrients, such as fatty acids and branched-chain amino acids.

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Concurrent depletion of Vps37 proteins evokes ESCRT-I destabilization and profound cellular stress responses

Cited by 17 publications

References 98 publications

ESCRT-I fuels lysosomal degradation to restrict TFEB/TFE3 signaling via the Rag-mTORC1 pathway

ESCRT-I fuels lysosomal degradation to restrict TFEB/TFE3 signaling via the Rag-mTORC1 pathway

VPS72, a member of VPS protein family, can be used as a new prognostic marker for hepatocellular carcinoma

NFκB and JNK pathways mediate metabolic adaptation upon ESCRT-I deficiency

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