Regulation of the divalent metal ion transporter via membrane budding

Mackenzie, Kimberly D.; Foot, Natalie; Anand, Sushma; Dalton, Hazel; Chaudhary, Natasha; Collins, Brett M.; Kumar, Sharad

doi:10.1038/celldisc.2016.11

Cited by 40 publications

(51 citation statements)

References 41 publications

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“…Similarly, EVs from Arrdc1 −/− MEFs had an average peak density of 149 and 168 nm for exosomes and ectosomes, respectively (Figure C). Consistent with our previous observations, Arrdc1 KO resulted in a reduction in the amount of EVs secreted (Figure C–E). Transmission electron microscopy confirmed the presence of EVs and similar shape could be observed between WT and Arrdc1 −/− cell‐derived EVs (Figure F).…”

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confidence: 93%

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Arrestin‐Domain Containing Protein 1 (Arrdc1) Regulates the Protein Cargo and Release of Extracellular Vesicles

Anand

Foot

et al. 2018

Proteomics

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Extracellular vesicles (EVs) are lipid-bilayered vesicles that are released by multiple cell types and contain nucleic acids and proteins. Very little is known about how the cargo is packaged into EVs. Ubiquitination of proteins is a key posttranslational modification that regulates protein stability and trafficking to subcellular compartments including EVs. Recently, arrestin-domain containing protein 1 (Arrdc1), an adaptor for the Nedd4 family of ubiquitin ligases, has been implicated in the release of ectosomes, a subtype of EV that buds from the plasma membrane. However, it is currently unknown whether Arrdc1 can regulate the release of exosomes, a class of EVs that are derived endocytically. Furthermore, it is unclear whether Arrdc1 can regulate the sorting of protein cargo into the EVs. Exosomes and ectosomes are isolated from mouse embryonic fibroblasts isolated from wild type and Arrdc1-deficient (Arrdc1 ) mice. Nanoparticle tracking analysis-based EV quantitation shows that Arrdc1 regulates the release of both exosomes and ectosomes. Proteomic analysis highlights the change in protein cargo in EVs upon deletion of Arrdc1. Functional enrichment analysis reveals the enrichment of mitochondrial proteins in ectosomes, while proteins implicated in apoptotic cleavage of cell adhesion proteins and formation of cornified envelope are significantly depleted in exosomes upon knockout of Arrdc1.

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confidence: 93%

“…Recently, Arrdc1 has been implicated in the biogenesis and budding of microvesicles shed from the plasma membrane . Furthermore, both Arrdc1 and Arrdc4 are considered as nonredundant positive regulators of EV release . However, very little is known about whether Arrdc proteins can regulate the biogenesis and release of exosomes.…”

mentioning

confidence: 99%

Arrestin‐Domain Containing Protein 1 (Arrdc1) Regulates the Protein Cargo and Release of Extracellular Vesicles

Anand

Foot

et al. 2018

Proteomics

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“…RNAi treatment was performed at 30% confluence, using Lipofectamine RNAiMAX (Invitrogen, Carlsbad, CA) according to the manufacturer’s instructions and analyzed 72 h after treatment. The following RNAi oligonucleotides from Eurogentec® were used: RASSF1A: si1: 5′-GACCUCUGUGGCGACUUCATT-3′ [ 66 ] & si2: GAACGUGGACGAGCCUGU [ 25 ]; GEFH1: 5′-GAAGGUAGCAGCCGUCUGU-3′ [ 25 ]; Rab11a: 5′-UGUCAGACAGA CGCGAAAA-3′ [ 52 ]; Rab11b: 5′-GCACCUGACCUAUGAGAAC-3′ [ 52 ]; Vimentin: 5′-UCACGAUGACCUUGAAUAA-3′ [ 57 ] and non-targeting control RNAi from Dharmacon. Transient transfection with plasmids encoding wild-type RASSF1A (pcDNA3-RASSF1A) and control mimic (Addgene®) were performed using Lipofectamine RNAiMAX (Invitrogen, Carlsbad, CA) following the manufacturer’s instructions and analyzed 24 h after transfection.…”

Section: Methodsmentioning

confidence: 99%

A role for RASSF1A in tunneling nanotube formation between cells through GEFH1/Rab11 pathway control

et al. 2018

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BackgroundBy allowing intercellular communication between cells, tunneling nanotubes (TNTs) could play critical role in cancer progression. If TNT formation is known to require cytoskeleton remodeling, key mechanism controlling their formation remains poorly understood.MethodsThe cells of human bronchial (HBEC-3, A549) or mesothelial (H2452, H28) lines are transfected with different siRNAs (inactive, anti-RASSF1A, anti-GEFH1 and / or anti-Rab11). At 48 h post-transfection, i) the number and length of the nanotubes per cell are quantified, ii) the organelles, previously labeled with specific tracers, exchanged via these structures are monitored in real time between cells cultured in 2D or 3D and in normoxia, hypoxia or in serum deprivation condition.ResultsWe report that RASSF1A, a key-regulator of cytoskeleton encoded by a tumor-suppressor gene on 3p chromosome, is involved in TNTs formation in bronchial and pleural cells since controlling proper activity of RhoB guanine nucleotide exchange factor, GEF-H1. Indeed, the GEF-H1 inactivation induced by RASSF1A silencing, leads to Rab11 accumulation and subsequent exosome releasing, which in turn contribute to TNTs formation. Finally, we provide evidence involving TNT formation in bronchial carcinogenesis, by reporting that hypoxia or nutriment privation, two almost universal conditions in human cancers, fail to prevent TNTs induced by the oncogenic RASSF1A loss of expression.ConclusionsThis finding suggests for the first time that loss of RASSF1A expression could be a potential biomarker for TNTs formation, such TNTs facilitating intercellular communication favoring multistep progression of bronchial epithelial cells toward overt malignancy.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0276-4) contains supplementary material, which is available to authorized users.

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“…For example, agents which reduce intracellular iron (e.g., membrane-permeable iron chelators) induce proteasomal degradation of ferritin, whilst those that limit iron uptake (e.g., impermeable iron chelators) promote degradation via the lysosome and activate autophagy (27). Iron import is also controlled by lysosomal or proteasomal degradation of TfR1 and DMT1 or by release from the plasma membrane into extracellular vesicles or endosomes (6,30,31). Therefore, posttranslational mechanisms are another level of control to ensure iron homeostasis.…”

Section: Iron Homeostasismentioning

confidence: 99%

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

et al. 2020

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Iron is an essential nutrient that plays a complex role in cancer biology. Iron metabolism must be tightly controlled within cells. Whilst fundamental to many cellular processes and required for cell survival, excess labile iron is toxic to cells. Increased iron metabolism is associated with malignant transformation, cancer progression, drug resistance and immune evasion. Depleting intracellular iron stores, either with the use of iron chelating agents or mimicking endogenous regulation mechanisms, such as microRNAs, present attractive therapeutic opportunities, some of which are currently under clinical investigation. Alternatively, iron overload can result in a form of regulated cell death, ferroptosis, which can be activated in cancer cells presenting an alternative anti-cancer strategy. This review focuses on alterations in iron metabolism that enable cancer cells to meet metabolic demands required during different stages of tumorigenesis in relation to metastasis and immune response. The strength of current evidence is considered, gaps in knowledge are highlighted and controversies relating to the role of iron and therapeutic targeting potential are discussed. The key question we address within this review is whether iron modulation represents a useful approach for treating metastatic disease and whether it could be employed in combination with existing targeted drugs and immune-based therapies to enhance their efficacy.

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Regulation of the divalent metal ion transporter via membrane budding

Cited by 40 publications

References 41 publications

Arrestin‐Domain Containing Protein 1 (Arrdc1) Regulates the Protein Cargo and Release of Extracellular Vesicles

Arrestin‐Domain Containing Protein 1 (Arrdc1) Regulates the Protein Cargo and Release of Extracellular Vesicles

A role for RASSF1A in tunneling nanotube formation between cells through GEFH1/Rab11 pathway control

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

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