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Open accessJournal ArticleDOI: 10.1096/FBA.2020-00138

Emerging roles for the autophagy machinery in extracellular vesicle biogenesis and secretion.

02 Mar 2021-Vol. 3, Iss: 5, pp 377-386
Abstract: Autophagy classically functions to maintain cell health during stressful conditions by targeting cytosolic components for degradation and recycling via lysosomal pathways. However, accumulating evidence also supports roles for autophagy-related genes (ATGs) in non-degradative processes including cellular secretion. Here, we review emerging roles for the autophagy machinery in regulating extracellular vesicle loading and secretion and discuss how functional coupling of these pathways may impact normal physiology and disease.

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Topics: Extracellular vesicle (63%), Autophagy (53%), Secretion (51%)
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Open accessJournal ArticleDOI: 10.1096/FBA.2021-00077
26 Jul 2021-
Abstract: Extracellular vesicles (EVs) are released by many different cell types throughout the body and play a role in a diverse range of biological processes. EVs circulating in blood as well as in other body fluids undergo dramatic alterations over an organism's lifespan that are only beginning to be elucidated. The exact nature of these changes is an area of active and intense investigation, but lacks clear consensus due to the substantial heterogeneity in EV subpopulations and insufficiencies in current technologies. Nonetheless, emerging evidence suggests that EVs regulate systemic aging as well as the pathophysiology of age-related diseases. Here, we review the current literature investigating EVs and aging with an emphasis on consequences for the maintenance of human healthspan. Intriguingly, the biological utility of EVs both in vitro and in vivo and across contexts depends on the states of the source cells or tissues. As such, EVs secreted by cells in an aged or pathological state may impose detrimental consequences on recipient cells, while EVs secreted by youthful or healthy cells may promote functional improvement. Thus, it is critical to understand both functions of EVs and tip the balance toward their beneficial effects as an antiaging intervention.

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Topics: Extracellular vesicle (51%)

3 Citations


Open accessJournal ArticleDOI: 10.1096/FBA.2021-00081
27 Aug 2021-
Abstract: To harmoniously coordinate the activities of all its different cell types, a multicellular organism critically depends on intercellular communication. One recently discovered mode of intercellular cross-talk is based on the exchange of "extracellular vesicles" (EVs). EVs are nano-sized heterogeneous lipid bilayer vesicles enriched in a variety of biomolecules that mediate short- and long-distance communication between different cells, and between cells and their environment. Numerous studies have demonstrated important aspects pertaining to the dynamics of their release, their uptake, and sub-cellular fate and roles in vitro. However, to demonstrate these and other aspects of EV biology in a relevant, fully physiological context in vivo remains challenging. In this review we analyze the state of the art of EV imaging in vivo, focusing in particular on zebrafish as a promising model to visualize, study, and characterize endogenous EVs in real-time and expand our understanding of EV biology at cellular and systems level.

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2 Citations


Open accessJournal ArticleDOI: 10.1016/J.EXPHEM.2021.08.004
Abstract: Highlights: Extracellular vesicles (EVs) are small lipid bilayer particles containing biologically important cargo and impart regulatory changes in target cells. Despite the importance of EVs in cellular communication, there remains a gap in our understanding of how EVs influence HSC fate and, in turn, how aging and longevity are affected. This review summarizes the current literature dealing with how age-altered intercellular communication mediated by EVs influences HSC biology.

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Topics: Vesicle (51%)

1 Citations


Open accessPosted ContentDOI: 10.1101/2021.08.12.456045
Tina Solvik1, Tan A. Nguyen1, Yu-Hsiu Tony Lin1, Timothy Marsh1  +4 moreInstitutions (1)
12 Aug 2021-bioRxiv
Abstract: The endosome-lysosome (endolysosome) system plays central roles in both autophagic degradation and secretory pathways, including the exocytic release of extracellular vesicles and particles (EVPs). Although previous work has revealed important interconnections between autophagy and EVP-mediated secretion, our molecular understanding of these secretory events during endolysosome inhibition remains incomplete. Here, we delineate a secretory autophagy pathway upregulated in response to endolysosomal inhibition that mediates the EVP-associated extracellular release of autophagic cargo receptors, including p62/SQSTM1. This extracellular secretion is highly regulated and critically dependent on multiple ATGs required for the progressive steps of early autophagosome formation as well as Rab27a-dependent exocytosis. Furthermore, the disruption of autophagosome maturation, either due to genetic inhibition of the autophagosome-to-autolyosome fusion machinery or blockade via the SARS-CoV2 viral protein ORF3a, is sufficient to induce robust EVP-associated secretion of autophagy cargo receptors. Finally, we demonstrate that this ATG-dependent, EVP-mediated secretion pathway buffers against the intracellular accumulation of autophagy cargo receptors when classical autophagic degradation is impaired. Based on these results, we propose that secretory autophagy via EVPs functions as an alternate route to clear sequestered material and maintain proteostasis in response to endolysosomal dysfunction or impaired autophagosome maturation.

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Topics: Autophagosome maturation (66%), Endolysosome (60%), Autophagy (59%) ... show more

Open accessPosted Content
Abstract: Clustering and community detection in networks are of broad interest and have been the subject of extensive research that spans several fields. We are interested in the relatively narrow question of detecting communities of scientific publications that are linked by citations. These publication communities can be used to identify scientists with shared interests who form communities of researchers. Building on the well-known k-core algorithm, we have developed a modular pipeline to find publication communities. We compare our approach to communities discovered by the widely used Leiden algorithm for community finding. Using a quantitative and qualitative approach, we evaluate community finding results on a citation network consisting of over 14 million publications relevant to the field of extracellular vesicles.

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93 results found


Open accessJournal ArticleDOI: 10.1016/J.MOLCEL.2010.09.023
22 Oct 2010-Molecular Cell
Abstract: Autophagy is a tightly regulated pathway involving the lysosomal degradation of cytoplasmic organelles or cytosolic components. This pathway can be stimulated by multiple forms of cellular stress, including nutrient or growth factor deprivation, hypoxia, reactive oxygen species, DNA damage, protein aggregates, damaged organelles, or intracellular pathogens. Both specific, stimulus-dependent and more general, stimulus-independent signaling pathways are activated to coordinate different phases of autophagy. Autophagy can be integrated with other cellular stress responses through parallel stimulation of autophagy and other stress responses by specific stress stimuli, through dual regulation of autophagy and other stress responses by multifunctional stress signaling molecules, and/or through mutual control of autophagy and other stress responses. Thus, autophagy is a cell biological process that is a central component of the integrated stress response.

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Topics: Integrated stress response (63%), Autophagy (62%), Programmed cell death (62%) ... show more

2,646 Citations


Open accessJournal ArticleDOI: 10.1038/NM.2753
Héctor Peinado1, Maša Alečković2, Simon Lavotshkin3, Irina Matei1  +25 moreInstitutions (8)
01 Jun 2012-Nature Medicine
Abstract: Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45(-)C-KIT(low/+)TIE2(+) bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process.

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Topics: Exosome (63%), Bone marrow (60%), Receptor tyrosine kinase (52%) ... show more

2,642 Citations


Open accessJournal ArticleDOI: 10.1038/NRM.2017.125
Abstract: Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising exosomes and microvesicles, which originate from the endosomal system or which are shed from the plasma membrane, respectively They are present in biological fluids and are involved in multiple physiological and pathological processes Extracellular vesicles are now considered as an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids and genetic material Knowledge of the cellular processes that govern extracellular vesicle biology is essential to shed light on the physiological and pathological functions of these vesicles as well as on clinical applications involving their use and/or analysis However, in this expanding field, much remains unknown regarding the origin, biogenesis, secretion, targeting and fate of these vesicles

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Topics: Extracellular vesicle (61%), Microvesicles (59%), Vesicle (56%) ... show more

2,353 Citations


Open accessJournal ArticleDOI: 10.1038/NRM2708
Abstract: Autophagy is a fundamental function of eukaryotic cells and is well conserved from yeast to humans. The most remarkable feature of autophagy is the synthesis of double membrane-bound compartments that sequester materials to be degraded in lytic compartments, a process that seems to be mechanistically distinct from conventional membrane traffic. The discovery of autophagy in yeast and the genetic tractability of this organism have allowed us to identify genes that are responsible for this process, which has led to the explosive growth of this research field seen today. Analyses of autophagy-related (Atg) proteins have unveiled dynamic and diverse aspects of mechanisms that underlie membrane formation during autophagy.

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Topics: Autophagy database (69%), ATG8 (58%), Atg1 (57%) ... show more

1,389 Citations


Open accessJournal ArticleDOI: 10.1126/SCIENCE.AAU6977
07 Feb 2020-Science
Abstract: The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.

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Topics: Exosome (68%), Microvesicles (53%)

1,179 Citations


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