Dihydroceramide Desaturase Promotes the Formation of Intraluminal Vesicles and Inhibits Autophagy to Increase Exosome Production

Wu, Chen‐Yi; Jhang, Jhih-Gang; Lin, Wan-Syuan; Lin, Chih-Wei; Chu, Li‐An; Chiang, Ann‐Shyn; Ho, Han‐Chen; Chan, Chih‐Chiang; Huang, Shu‐Yi

doi:10.2139/ssrn.3865281

Cited by 3 publications

(4 citation statements)

References 34 publications

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“…Although TNF-R1 can be released into exosomes [224], the exact mechanism that regulates the nSMase2-ceramide pathway on the limiting membrane of MVBs is still obscure. STARD11 and DEGS1 mediate ceramide trafficking to or production on MVBs, separately, but robust evidence remains to be established, and the functions of these proteins in cancer remain unclear [39,225,226]. Therefore, the different functions of nSMase2 might depend on its particular cellular location.…”

Section: Targeting Nsmase2mentioning

confidence: 99%

Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer

et al. 2022

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Exosomes are well-known key mediators of intercellular communication and contribute to various physiological and pathological processes. Their biogenesis involves four key steps, including cargo sorting, MVB formation and maturation, transport of MVBs, and MVB fusion with the plasma membrane. Each process is modulated through the competition or coordination of multiple mechanisms, whereby diverse repertoires of molecular cargos are sorted into distinct subpopulations of exosomes, resulting in the high heterogeneity of exosomes. Intriguingly, cancer cells exploit various strategies, such as aberrant gene expression, posttranslational modifications, and altered signaling pathways, to regulate the biogenesis, composition, and eventually functions of exosomes to promote cancer progression. Therefore, exosome biogenesis-targeted therapy is being actively explored. In this review, we systematically summarize recent progress in understanding the machinery of exosome biogenesis and how it is regulated in the context of cancer. In particular, we highlight pharmacological targeting of exosome biogenesis as a promising cancer therapeutic strategy.

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Section: Targeting Nsmase2mentioning

confidence: 99%

Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer

et al. 2022

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“…Our experiments showing that autophagy supplies peroxidated lipids for release points to exocytosis of the autolysosomes as opposed to late-endosomes or multivesicular bodies. Also, inhibitors of early-stage autophagy stimulate extracellular vesicle release (Wu et al, 2021) but decrease lipid hydroperoxide and iron release further strengthens this conclusion. While the lipid-protein particles in the media resemble the indigestible material that remains in autolysosomes, similar to residual bodies and lipofuscin (U.…”

Section: Discussionmentioning

confidence: 52%

“…However, given that 3-MA stimulates exosome release (Fig. S5, G and H) (Wu et al, 2021), yet decreases lipid hydroperoxide and iron release (Fig. 7, L and 8, F), we reason that exosomes may play only a minor role in protecting neurons from lipid peroxidation.…”

Section: Resultsmentioning

confidence: 90%

Autolysosomal exocytosis of lipids protect neurons from ferroptosis

Ralhan

Chang

Moulton

et al. 2022

Preprint

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During oxidative stress neurons release lipids that are internalized by glia. Defects in this coordinated process play an important role in several neurodegenerative diseases. Yet, the mechanisms of lipid release and its consequences on neuronal health are unclear. Here, we demonstrate that lipid-protein particle release by autolysosome exocytosis protects neurons from ferroptosis, a form of cell death driven by lipid peroxidation. We show that during oxidative stress, peroxidated lipids and iron are released from neurons by autolysosomal exocytosis which requires the exocytic machinery; VAMP7 and syntaxin 4. We observe membrane-bound lipid-protein particles by TEM and demonstrate that these particles are released from neurons using cryoEM. Failure to release these lipid-protein particles causes lipid hydroperoxide and iron accumulation and sensitizes neurons to ferroptosis. Our results reveal how neurons protect themselves from peroxidated lipids. Given the number of brain pathologies that involve ferroptosis, defects in this pathway likely play a key role in the pathophysiology of neurodegenerative disease.

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“…Overexpression of Ifc inhibits autophagy to increase exosome secretion, but Ifc is not involved in cargo sorting. [23] Continuous Cer catabolism to produce sphingosine 1-phosphate is required to sort exosomal cargo into ILVs, and sustained activation of Gi-coupled S1P receptors on the MVE is essential for sorting cargo into ILVs designed to release exosomes. [24] The cer-rich membrane structural domain serves not only as a permissive environment to promote ILV formation but also as a platform to facilitate the recruitment of ESCRT components.…”

Section: Exosome Formationmentioning

confidence: 99%

Exosomes: A new option for osteoporosis treatment

et al. 2022

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Osteoporosis is a systemic bone disease characterized by reduced bone mass and destruction of bone microarchitecture, leading to increased bone fragility and susceptibility to fracture. However, the pathogenesis and molecular mechanisms of this disease remain unclear. Extracellular vesicles, structures originating from the plasma membrane and ranging from 30 nm to 5 µm in diameter, play an important role in intercellular communication in the bone microenvironment. Exosomes are extracellular vesicles that deliver cargo molecules, including endogenous proteins, lipids and nucleic acids. These cargo molecules are encapsulated in a lipid bilayer and internalized by target cells through receptor-ligand interactions or lipid membrane fusion. With the advancement of exosome research, exosome therapy for osteoporosis is fast becoming a research hotspot for researchers. This review aims to discuss the role of exosomes in the pathogenesis of osteoporosis. In addition, emerging diagnostic and therapeutic properties of exosomes are described to highlight the potential role of exosomes in osteoporosis.

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Dihydroceramide Desaturase Promotes the Formation of Intraluminal Vesicles and Inhibits Autophagy to Increase Exosome Production

Cited by 3 publications

References 34 publications

Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer

Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer

Autolysosomal exocytosis of lipids protect neurons from ferroptosis

Exosomes: A new option for osteoporosis treatment

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