Role of Ceramides and Lysosomes in Extracellular Vesicle Biogenesis, Cargo Sorting and Release

Horbay, Rostyslav; Hamraghani, Ali; Ermini, Leonardo; Holcik, Sophie; Beug, Shawn T.; Yeganeh, Behzad

doi:10.3390/ijms232315317

Cited by 36 publications

(23 citation statements)

References 202 publications

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“…As per our estimation, the membrane of approximately 60 EVs equates to the ciliary membrane (Figure S3A). Ceramide is a pivotal membrane lipid essential for EV formation 2,18 . Ceramide is also an important lipid for cilia formation, ciliary length and ciliary signaling 19 .…”

Section: Resultsmentioning

confidence: 99%

Ciliary intrinsic mechanisms regulate dynamic ciliary extracellular vesicle release from sensory neurons

Wang,

Saul,

Nikonorova

et al. 2023

Preprint

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SummaryCilia-derived extracellular vesicles (EVs) contain signaling proteins and act in intercellular communication. Polycystin-2 (PKD-2), a transient receptor potential channel, is a conserved ciliary EVs cargo.Caenorhabditis elegansserves as a model for studying ciliary EV biogenesis and function.C. elegansmales release EVs in a mechanically-induced manner and deposit PKD-2-labeled EVs onto the hermaphrodite vulva during mating, suggesting an active release process. Here, we study the dynamics of ciliary EV release using time-lapse imaging and find that cilia can sustain the release of PKD-2-labeled EVs for a two-hour duration. Intriguingly, this extended release doesn’t require neuronal synaptic transmission. Instead, ciliary intrinsic mechanisms regulate PKD-2 ciliary membrane replenishment and dynamic EV release. The ciliary kinesin-3 motor KLP-6 is necessary for both initial and extended ciliary EV release, while the transition zone protein NPHP-4 is required only for sustained EV release. The dihydroceramide desaturase DEGS1/2 ortholog TTM-5 is highly expressed in the EV-releasing sensory neurons, localizes to cilia, and is required for sustained but not initial ciliary EV release, implicating ceramide in ciliary ectocytosis. The study offers a comprehensive portrait of real-time ciliary EV release, and mechanisms supporting cilia as proficient EV release platforms.

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Section: Resultsmentioning

confidence: 99%

Ciliary intrinsic mechanisms regulate dynamic ciliary extracellular vesicle release from sensory neurons

Wang,

Saul,

Nikonorova

et al. 2023

Preprint

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“…Numerous studies have also shown that phosphoinositides, ceramides, and the lipid composition of the endosomal membrane as a whole are key factors in the biogenesis of ILVs [ 38 , 39 ]. It is also worth mentioning that ESCRT-independent mechanisms have been delineated as alternative systems for the formation of ILVs, and that vesicle release by cells could also occur from lysosomes [ 40 , 41 , 42 ]. In addition, a process involving tetraspanin enrichment appears to be important for membrane remodeling and ILVs formation [ 43 , 44 ].…”

Section: Exosomes Are Small Specialized Extracellular Vesicles (Evs)mentioning

confidence: 99%

Exosome-Mediated Antigen Delivery: Unveiling Novel Strategies in Viral Infection Control and Vaccine Design

El Safadi,

Mokhtari,

Krejbich

et al. 2024

Vaccines

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Exosomes are small subtypes of extracellular vesicles (EVs) naturally released by different types of cells into their environment. Their physiological roles appear to be multiple, yet many aspects of their biological activities remain to be understood. These vesicles can transport and deliver a variety of cargoes and may serve as unconventional secretory vesicles. Thus, they play a crucial role as important vectors for intercellular communication and the maintenance of homeostasis. Exosome production and content can vary under several stresses or modifications in the cell microenvironment, influencing cellular responses and stimulating immunity. During infectious processes, exosomes are described as double-edged swords, displaying both beneficial and detrimental effects. Owing to their tractability, the analysis of EVs from multiple biofluids has become a booming tool for monitoring various pathologies, from infectious to cancerous origins. In this review, we present an overview of exosome features and discuss their particular and ambiguous functions in infectious contexts. We then focus on their properties as diagnostic or therapeutic tools. In this regard, we explore the capacity of exosomes to vectorize immunogenic viral antigens and their function in mounting adaptive immune responses. As exosomes provide interesting platforms for antigen presentation, we further review the available data on exosome engineering, which enables peptides of interest to be exposed at their surface. In the light of all these data, exosomes are emerging as promising avenues for vaccine strategies.

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“…20 Several research groups have investigated the feasibility of using EV to transport pharmaceuticals, nucleic acids, and proteins for therapeutic purposes. 21,22 In this study, we identified potential candidate genes using an in vivo genetic loss-of-function screening approach based on CRISPR-Cas9 genome editing to identify genes that increase the sensitivity or cause radioresistance in an orthotopic GBM model. Ferroptosis, triggered by the enzyme glutathione synthetase (GSS), has been shown to be a determinant in radiosensitization.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, EV proteins include CD47, a transmembrane protein linked with integrins that helps shield cells from phagocytosis . Several research groups have investigated the feasibility of using EV to transport pharmaceuticals, nucleic acids, and proteins for therapeutic purposes. , …”

Section: Introductionmentioning

confidence: 99%

Engineered Extracellular Vesicle-Delivered CRISPR/Cas9 for Radiotherapy Sensitization of Glioblastoma

Liu,

Cao,

Wang

et al. 2023

ACS Nano

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Radiotherapy is a mainstay of glioblastoma (GBM) treatment; however, the development of therapeutic resistance has hampered the efficacy of radiotherapy, suggesting that additional treatment strategies are needed. Here, an in vivo loss-of-function genome-wide CRISPR screen was carried out in orthotopic tumors in mice subjected to radiation treatment to identify synthetic lethal genes associated with radiotherapy. Using functional screening and transcriptome analyses, glutathione synthetase (GSS) was found to be a potential regulator of radioresistance through ferroptosis. High GSS levels were closely related to poor prognosis and relapse in patients with glioma. Mechanistic studies demonstrated that GSS was associated with the suppression of radiotherapy-induced ferroptosis in glioma cells. The depletion of GSS resulted in the disruption of glutathione (GSH) synthesis, thereby causing the inactivation of GPX4 and iron accumulation, thus enhancing the induction of ferroptosis upon radiotherapy treatment. Moreover, to overcome the obstacles to broad therapeutic translation of CRISPR editing, we report a previously unidentified genome editing delivery system, in which Cas9 protein/sgRNA complex was loaded into Angiopep-2 (Ang) and the trans-activator of the transcription (TAT) peptide dual-modified extracellular vesicle (EV), which not only targeted the blood–brain barrier (BBB) and GBM but also permeated the BBB and penetrated the tumor. Our encapsulating EVs showed encouraging signs of GBM tissue targeting, which resulted in high GSS gene editing efficiency in GBM (up to 67.2%) with negligible off-target gene editing. These results demonstrate that a combination of unbiased genetic screens, and CRISPR-Cas9-based gene therapy is feasible for identifying potential synthetic lethal genes and, by extension, therapeutic targets.

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Role of Ceramides and Lysosomes in Extracellular Vesicle Biogenesis, Cargo Sorting and Release

Cited by 36 publications

References 202 publications

Ciliary intrinsic mechanisms regulate dynamic ciliary extracellular vesicle release from sensory neurons

Ciliary intrinsic mechanisms regulate dynamic ciliary extracellular vesicle release from sensory neurons

Exosome-Mediated Antigen Delivery: Unveiling Novel Strategies in Viral Infection Control and Vaccine Design

Engineered Extracellular Vesicle-Delivered CRISPR/Cas9 for Radiotherapy Sensitization of Glioblastoma

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