scholarly journals To be or not to be... secreted as exosomes, a balance finely tuned by the mechanisms of biogenesis

2018 ◽  
Vol 62 (2) ◽  
pp. 177-191 ◽  
Author(s):  
Roberta Palmulli ◽  
Guillaume van Niel
Keyword(s):  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Intracellular Trafficking ◽  
Membrane Vesicles ◽  
Lysosomal Degradation ◽  
Trafficking Pathway ◽  
Exosome Biogenesis ◽  
Cargo Proteins ◽  
Communication Pathway ◽  
Multivesicular Endosomes

The release of extracellular vesicles such as exosomes provides an attractive intercellular communication pathway. Exosomes are 30- to 150-nm membrane vesicles that are generated in endosomal compartment and act as intercellular mediators in both physiological and pathological context. Despite the growing interest in exosome functions, the mechanisms responsible for their biogenesis and secretion are still not completely understood. Knowledge about these mechanisms is important because they control the composition, and hence the function and secretion, of exosomes. Exosomes are produced as intraluminal vesicles in extremely dynamic endosomal organelles, which undergo various maturation processes in order to form multivesicular endosomes. Notably, the function of multivesicular endosomes is balanced between exosome secretion and lysosomal degradation. In the present review, we present and discuss each intracellular trafficking pathway that has been reported or proposed as regulating exosome biogenesis, with a particular focus on the importance of endosomal dynamics in sorting out cargo proteins to exosomes and to the secretion of multivesicular endosomes. An overall picture reveals several key mechanisms, which mainly act at the crossroads of endosomal pathways as regulatory checkpoints of exosome biogenesis.

scholarly journals LAMP2A regulates the loading of proteins into exosomes.

2021 ◽  
Author(s):  
Joao Vasco Ferreira ◽  
Ana da Rosa Soares ◽  
Jose S. Ramalho ◽  
Catarina Maximo Carvalho ◽  
Maria Helena Cardoso ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Membrane Protein ◽  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Fluorescent Proteins ◽  
Cell Types ◽  
Zebrafish Larvae ◽  
Escrt Machinery ◽  
Bioactive Proteins ◽  
Exosome Biogenesis

Exosomes are extracellular vesicles of endosomal origin released by virtually all cell types across metazoans. Exosomes are active vehicles of intercellular communication and can transfer lipids, RNAs and proteins between different cells, tissues or organs. However, the mechanisms that regulate the selective loading of cytosolic proteins into these vesicles are still largely unknow. Here we describe a mechanism whereby proteins containing a pentapeptide sequence, biochemically related to the KFERQ-motif, are loaded into a subpopulation of exosomes in a process that is dependent on the membrane protein LAMP2A. Moreover, this mechanism is independent of the ESCRT machinery components TSG101 and VPS4b and dependent on HSC70, CD63, Alix, Syntenin-1, Rab31 and ceramides. The transcription factor and master regulator of hypoxia HIF1A is loaded into exosomes by this mechanism to transport hypoxia signaling to normoxic cells. Additionally, by tagging fluorescent proteins with KFERQ-like sequences we were able to follow inter-organ transfer of exosomes in zebrafish larvae. Our findings identify LAMP2A as a key component in exosome biogenesis while opening new avenues for exosome engineering by allowing the loading of bioactive proteins by tagging them with KFERQ-like motifs.

scholarly journals A conserved ATG2-GABARAP interaction is critical for phagophore closure

2019 ◽  
Author(s):  
Mihaela Bozic ◽  
Luuk van den Bekerom ◽  
Beth A. Milne ◽  
Nicola Goodman ◽  
Lisa Roberston ◽  
...  
Keyword(s):  
Intracellular Trafficking ◽  
Transition Point ◽  
Wild Type ◽  
Lysosomal Degradation ◽  
Autophagy Flux ◽  
Knock Out ◽  
Trafficking Pathway ◽  
Close Proximity ◽  
Key Players ◽  
Periods Of Stress

AbstractThe intracellular trafficking pathway, macroautophagy, acts as a recycling and disposal service that can be upregulated during periods of stress, to maintain cellular homeostasis. An essential transition point in the pathway is the sealing of the immature phagophore to form an autophagosome, isolating unwanted cargo prior to lysosomal degradation. However, little mechanistic detail is known about phagophore closure. Human ATG2A and ATG2B proteins, through their interaction with WIPI proteins, are thought to be key players during phagophore closure. We have identified a highly-conserved motif driving the interaction between human ATG2 and GABARAP proteins that is in close proximity to the ATG2-WIPI4 interaction site. We show that the ATG2-GABARAP interaction mutants are unable to close phagophores resulting in blocked autophagy, similar to ATG2A/ATG2B double knock-out cells. In contrast, the ATG2-WIPI4 interaction mutant fully restored phagophore closure and autophagy flux, similar to wild type ATG2. Taken together, we provide new mechanistic insights to the requirements for ATG2 function at the phagophore and suggest that an ATG2-GABARAP interaction is essential for phagophore closure, whereas ATG2-WIPI4 interaction is dispensable.

scholarly journals Extracellular vesicles: An emerging platform in gram-positive bacteria

2020 ◽  
Vol 7 (12) ◽  
pp. 312-322
Author(s):  
Swagata Bose ◽  
Shifu Aggarwal ◽  
Durg Vijai Singh ◽  
Narottam Acharya
Keyword(s):  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Pathogenic Bacteria ◽  
Membrane Vesicles ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Gram Positive Bacteria ◽  
Functional Aspects ◽  
As Stress

Extracellular vesicles (EV), also known as membrane vesicles, are produced as an end product of secretion by both pathogenic and non-pathogenic bacteria. Several reports suggest that archaea, gram-negative bacteria, and eukaryotic cells secrete membrane vesicles as a means for cell-free intercellular communication. EVs influence intercellular communication by transferring a myriad of biomolecules including genetic information. Also, EVs have been implicated in many phenomena such as stress response, intercellular competition, lateral gene transfer, and pathogenicity. However, the cellular process of secreting EVs in gram-positive bacteria is less studied. A notion with the thick cell-walled microbes such as gram-positive bacteria is that the EV release is impossible among them. The role of gram-positive EVs in health and diseases is being studied gradually. Being nano-sized, the EVs from gram-positive bacteria carry a diversity of cargo compounds that have a role in bacterial competition, survival, invasion, host immune evasion, and infection. In this review, we summarise the current understanding of the EVs produced by gram-positive bacteria. Also, we discuss the functional aspects of these components while comparing them with gram-negative bacteria.

scholarly journals Extracellular Vesicle Quantification and Characterization: Common Methods and Emerging Approaches

2019 ◽  
Vol 6 (1) ◽  
pp. 7 ◽  
Author(s):  
Thomas Hartjes ◽  
Serhii Mytnyk ◽  
Guido Jenster ◽  
Volkert van Steijn ◽  
Martin van Royen
Keyword(s):  
Physical Properties ◽  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Therapeutic Potential ◽  
Membrane Vesicles ◽  
Extracellular Vesicle ◽  
Medical Applications ◽  
Accurate Assessment ◽  
Further Development

Extracellular vesicles (EVs) are a family of small membrane vesicles that carry information about cells by which they are secreted. Growing interest in the role of EVs in intercellular communication, but also in using their diagnostic, prognostic and therapeutic potential in (bio) medical applications, demands for accurate assessment of their biochemical and physical properties. In this review, we provide an overview of available technologies for EV analysis by describing their working principles, assessing their utility in EV research and summarising their potential and limitations. To emphasise the innovations in EV analysis, we also highlight the unique possibilities of emerging technologies with high potential for further development.

scholarly journals ROR1 sustains multivesicular endosomes by interacting with HRS and STAM1

2020 ◽  
Author(s):  
Tomoya Yamaguchi ◽  
Masatoshi Yamamoto ◽  
Masaya Yamazaki ◽  
Naoki Tani ◽  
Mai Sakamoto ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Cancer Cells ◽  
Receptor Tyrosine Kinase ◽  
Orphan Receptor ◽  
Lysosomal Degradation ◽  
Exosome Biogenesis ◽  
Essential Components ◽  
Embryonic Antigen ◽  
Survival Signaling ◽  
Multivesicular Endosomes

Abstract The receptor tyrosine kinase-like orphan receptor 1 (ROR1) regulates caveolae formation and caveolae-dependent endocytosis by interacting with caveolae components, which in turn sustains pro-survival signaling toward AKT from multiple RTKs, including EGFR, and MET. We report here a novel function of ROR1 as a scaffold for HRS and STAM1, two essential components of ESCRT-0. The present results show that ROR1 facilitates interactions of HRS and STAM1, thereby preventing the lysosomal degradation of HRS. Furthermore, interaction of ROR1 with STAM1 was found to be required to sustain binding of ROR1 to HRS as well as HRS subcellular localization. Additionally, ROR1 localized in both the limiting membrane and intraluminal vesicles (ILVs) of Rab5-induced multivesicular endosomes (MVEs) containing HRS, CD63, and EEA1 was found to regulate the formation of Rab5-induced MVEs by an association with the GTP-bound form of Rab5 in cancer cells. Notably, ROR1 depletion inhibits CD63-positive MVEs formation and reduces exosomes release. Our findings provide the first evidence that the onco-embryonic antigen receptor ROR1 regulates exosome biogenesis via MVE formation in cancer cells.

scholarly journals Role for extracellular vesicles in the tumour microenvironment

2017 ◽  
Vol 373 (1737) ◽  
pp. 20160488 ◽  
Author(s):  
Ana O'Loghlen
Keyword(s):  
Cardiovascular Diseases ◽  
Nucleic Acids ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Intercellular Communication ◽  
Membrane Vesicles ◽  
Tumour Microenvironment ◽  
Cellular Behaviour ◽  
Almost All ◽  
Behaviour Changes

Extracellular vesicles (EVs) are small-membrane vesicles secreted by most cells types with the role to provide intercellular communication both locally and systemically. The transfer of their content between cells, which includes nucleic acids, proteins and lipids, confers the means for these interactions and induces significant cellular behaviour changes in the receiving cell. EVs are implicated in the regulation of numerous physiological and pathological processes, including development and neurological and cardiovascular diseases. Importantly, it has been shown that EV signalling is essential in almost all the steps necessary for the progress of carcinomas, from primary tumours to metastasis. In this review, we will focus on the latest findings for EV biology in relation to cancer progression and the tumour microenvironment. This article is part of the discussion meeting issue ‘Extracellular vesicles and the tumour microenvironment’.

scholarly journals Exosomes: Looking back three decades and into the future

2013 ◽  
Vol 200 (4) ◽  
pp. 367-371 ◽  
Author(s):  
Clifford V. Harding ◽  
John E. Heuser ◽  
Philip D. Stahl
Keyword(s):  
Intercellular Communication ◽  
Membrane Vesicles ◽  
Exciting Current ◽  
The Future ◽  
Multivesicular Endosomes ◽  
Looking Back

Exosomes are extracellular membrane vesicles whose biogenesis by exocytosis of multivesicular endosomes was discovered in 1983. Since their discovery 30 years ago, it has become clear that exosomes contribute to many aspects of physiology and disease, including intercellular communication. We discuss the initial experiments that led to the discovery of exosomes and highlight some of the exciting current directions in the field.

scholarly journals Helicobacter pylori Outer Membrane Vesicles and Extracellular Vesicles from Helicobacter pylori-Infected Cells in Gastric Disease Development

2021 ◽  
Vol 22 (9) ◽  
pp. 4823
Author(s):  
María Fernanda González ◽  
Paula Díaz ◽  
Alejandra Sandoval-Bórquez ◽  
Daniela Herrera ◽  
Andrew F. G. Quest
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Outer Membrane ◽  
Extracellular Vesicles ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Host Cells ◽  
Gastric Epithelium ◽  
Infected Cells ◽  
H Pylori

Extracellular vesicles (EVs) are cell-derived vesicles important in intercellular communication that play an essential role in host-pathogen interactions, spreading pathogen-derived as well as host-derived molecules during infection. Pathogens can induce changes in the composition of EVs derived from the infected cells and use them to manipulate their microenvironment and, for instance, modulate innate and adaptive inflammatory immune responses, both in a stimulatory or suppressive manner. Gastric cancer is one of the leading causes of cancer-related deaths worldwide and infection with Helicobacter pylori (H. pylori) is considered the main risk factor for developing this disease, which is characterized by a strong inflammatory component. EVs released by host cells infected with H. pylori contribute significantly to inflammation, and in doing so promote the development of disease. Additionally, H. pylori liberates vesicles, called outer membrane vesicles (H. pylori-OMVs), which contribute to atrophia and cell transformation in the gastric epithelium. In this review, the participation of both EVs from cells infected with H. pylori and H. pylori-OMVs associated with the development of gastric cancer will be discussed. By deciphering which functions of these external vesicles during H. pylori infection benefit the host or the pathogen, novel treatment strategies may become available to prevent disease.

scholarly journals Bacterial Membrane Vesicles in Pneumonia: From Mediators of Virulence to Innovative Vaccine Candidates

2021 ◽  
Vol 22 (8) ◽  
pp. 3858
Author(s):  
Felix Behrens ◽  
Teresa C. Funk-Hilsdorf ◽  
Wolfgang M. Kuebler ◽  
Szandor Simmons
Keyword(s):  
Extracellular Vesicles ◽  
Inflammatory Responses ◽  
Significant Proportion ◽  
Treatment Strategies ◽  
Membrane Vesicles ◽  
Multidrug Resistant ◽  
Biochemical Properties ◽  
Outer Membrane Vesicles ◽  
Vaccine Candidates ◽  
Treatment Regimens

Pneumonia due to respiratory infection with most prominently bacteria, but also viruses, fungi, or parasites is the leading cause of death worldwide among all infectious disease in both adults and infants. The introduction of modern antibiotic treatment regimens and vaccine strategies has helped to lower the burden of bacterial pneumonia, yet due to the unavailability or refusal of vaccines and antimicrobials in parts of the global population, the rise of multidrug resistant pathogens, and high fatality rates even in patients treated with appropriate antibiotics pneumonia remains a global threat. As such, a better understanding of pathogen virulence on the one, and the development of innovative vaccine strategies on the other hand are once again in dire need in the perennial fight of men against microbes. Recent data show that the secretome of bacteria consists not only of soluble mediators of virulence but also to a significant proportion of extracellular vesicles—lipid bilayer-delimited particles that form integral mediators of intercellular communication. Extracellular vesicles are released from cells of all kinds of organisms, including both Gram-negative and Gram-positive bacteria in which case they are commonly termed outer membrane vesicles (OMVs) and membrane vesicles (MVs), respectively. (O)MVs can trigger inflammatory responses to specific pathogens including S. pneumonia, P. aeruginosa, and L. pneumophila and as such, mediate bacterial virulence in pneumonia by challenging the host respiratory epithelium and cellular and humoral immunity. In parallel, however, (O)MVs have recently emerged as auspicious vaccine candidates due to their natural antigenicity and favorable biochemical properties. First studies highlight the efficacy of such vaccines in animal models exposed to (O)MVs from B. pertussis, S. pneumoniae, A. baumannii, and K. pneumoniae. An advanced and balanced recognition of both the detrimental effects of (O)MVs and their immunogenic potential could pave the way to novel treatment strategies in pneumonia and effective preventive approaches.

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