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Article ; Online: Q&A: What are exosomes, exactly?

Edgar, James R

BMC biology

2016 Volume 14, Page(s) 46

Abstract: Exosomes are extracellular vesicles first described as such 30 years ago and since implicated in cell-cell communication and the transmission of disease states, and explored as a means of drug discovery. Yet fundamental questions about their biology ... ...

Abstract	Exosomes are extracellular vesicles first described as such 30 years ago and since implicated in cell-cell communication and the transmission of disease states, and explored as a means of drug discovery. Yet fundamental questions about their biology remain unanswered. Here I explore what exosomes are, highlight the difficulties in studying them and explain the current definition and some of the outstanding issues in exosome biology.
MeSH term(s)	Animals ; Biomarkers/metabolism ; Disease ; Exosomes/metabolism ; Exosomes/ultrastructure ; Humans ; Models, Biological
Chemical Substances	Biomarkers
Language	English
Publishing date	2016-06-13
Publishing country	England
Document type	Journal Article
ISSN	1741-7007
ISSN (online)	1741-7007
DOI	10.1186/s12915-016-0268-z
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Article: Spastin MIT Domain Disease-Associated Mutations Disrupt Lysosomal Function.

Allison, Rachel / Edgar, James R / Reid, Evan

Frontiers in neuroscience

2019 Volume 13, Page(s) 1179

Abstract: The hereditary spastic paraplegias (HSPs) are genetic motor neuron diseases characterized by progressive degeneration of corticospinal tract axons. Mutations in SPAST, encoding the microtubule-severing ATPase spastin, are the most common causes of HSP. ... ...

Abstract	The hereditary spastic paraplegias (HSPs) are genetic motor neuron diseases characterized by progressive degeneration of corticospinal tract axons. Mutations in SPAST, encoding the microtubule-severing ATPase spastin, are the most common causes of HSP. The broad SPAST mutational spectrum indicates a haploinsufficiency pathogenic mechanism in most cases. Most missense mutations cluster in the ATPase domain, where they disrupt the protein's ability to sever microtubules. However, several putative missense mutations in the protein's microtubule interacting and trafficking (MIT) domain have also been described, but the pathogenicity of these mutations has not been verified with functional studies. Spastin promotes endosomal tubule fission, and defects in this lead to lysosomal enzyme mistrafficking and downstream lysosomal abnormalities. We investigated the function of three disease-associated spastin MIT mutants and found that none was able to promote normal endosomal tubule fission, lysosomal enzyme receptor trafficking, or lysosomal morphology. One of the mutations affected recruitment of spastin to endosomes, a property that requires the canonical function of the MIT domain in binding endosomal sorting complex required for transport (ESCRT)-III proteins. However, the other mutants did not affect spastin's endosomal recruitment, raising the possibility of pathologically important non-canonical roles for the MIT domain. In conclusion, we demonstrate that spastin MIT mutants cause functional abnormalities related to the pathogenesis of HSP. These mutations do not directly affect spastin's microtubule-severing capacity, and so we identify a new molecular pathological mechanism by which spastin mutations may cause disease.
Language	English
Publishing date	2019-11-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2019.01179
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Article: Exploiting Connections for Viral Replication.

Wong, Louise H / Edgar, James R / Martello, Andrea / Ferguson, Brian J / Eden, Emily R

Frontiers in cell and developmental biology

2021 Volume 9, Page(s) 640456

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the COVID-19 (coronavirus disease 2019) pandemic, is a positive strand RNA (+RNA) virus. Like other +RNA viruses, SARS-CoV-2 is dependent on host cell metabolic machinery to ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the COVID-19 (coronavirus disease 2019) pandemic, is a positive strand RNA (+RNA) virus. Like other +RNA viruses, SARS-CoV-2 is dependent on host cell metabolic machinery to survive and replicate, remodeling cellular membranes to generate sites of viral replication. Viral RNA-containing double-membrane vesicles (DMVs) are a striking feature of +RNA viral replication and are abundant in SARS-CoV-2-infected cells. Their generation involves rewiring of host lipid metabolism, including lipid biosynthetic pathways. Viruses can also redirect lipids from host cell organelles; lipid exchange at membrane contact sites, where the membranes of adjacent organelles are in close apposition, has been implicated in the replication of several +RNA viruses. Here we review current understanding of DMV biogenesis. With a focus on the exploitation of contact site machinery by +RNA viruses to generate replication organelles, we discuss evidence that similar mechanisms support SARS-CoV-2 replication, protecting its RNA from the host cell immune response.
Language	English
Publishing date	2021-03-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2021.640456
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Article ; Online: Bioengineered small extracellular vesicles deliver multiple SARS-CoV-2 antigenic fragments and drive a broad immunological response.

Jackson, Hannah K / Long, Heather M / Yam-Puc, Juan Carlos / Palmulli, Roberta / Haigh, Tracey A / Gerber, Pehuén Pereyra / Lee, Jin S / Matheson, Nicholas J / Young, Lesley / Trowsdale, John / Lo, Mathew / Taylor, Graham S / Thaventhiran, James E / Edgar, James R

Journal of extracellular vesicles

2024 Volume 13, Issue 2, Page(s) e12412

Abstract: The COVID-19 pandemic highlighted the clear risk that zoonotic viruses pose to global health and economies. The scientific community responded by developing several efficacious vaccines which were expedited by the global need for vaccines. The emergence ... ...

Abstract	The COVID-19 pandemic highlighted the clear risk that zoonotic viruses pose to global health and economies. The scientific community responded by developing several efficacious vaccines which were expedited by the global need for vaccines. The emergence of SARS-CoV-2 breakthrough infections highlights the need for additional vaccine modalities to provide stronger, long-lived protective immunity. Here we report the design and preclinical testing of small extracellular vesicles (sEVs) as a multi-subunit vaccine. Cell lines were engineered to produce sEVs containing either the SARS-CoV-2 Spike receptor-binding domain, or an antigenic region from SARS-CoV-2 Nucleocapsid, or both in combination, and we tested their ability to evoke immune responses in vitro and in vivo. B cells incubated with bioengineered sEVs were potent activators of antigen-specific T cell clones. Mice immunised with sEVs containing both sRBD and Nucleocapsid antigens generated sRBD-specific IgGs, nucleocapsid-specific IgGs, which neutralised SARS-CoV-2 infection. sEV-based vaccines allow multiple antigens to be delivered simultaneously resulting in potent, broad immunity, and provide a quick, cheap, and reliable method to test vaccine candidates.
MeSH term(s)	Animals ; Humans ; Mice ; SARS-CoV-2 ; Pandemics ; COVID-19 ; Extracellular Vesicles ; Vaccines
Chemical Substances	Vaccines
Language	English
Publishing date	2024-02-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2683797-3
ISSN	2001-3078 ; 2001-3078
ISSN (online)	2001-3078
ISSN	2001-3078
DOI	10.1002/jev2.12412
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Article: A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease.

Lim, Kyungtae / Rutherford, Eimear N / Sun, Dawei / Van den Boomen, Dick J H / Edgar, James R / Bang, Jae Hak / Matesic, Lydia E / Lee, Joo-Hyeon / Lehner, Paul J / Marciniak, Stefan J / Rawlins, Emma L / Dickens, Jennifer A

bioRxiv : the preprint server for biology

2023

Abstract: Alveolar type 2 (AT2) cells maintain lung health by acting as stem cells and producing pulmonary ... ...

Abstract	Alveolar type 2 (AT2) cells maintain lung health by acting as stem cells and producing pulmonary surfactant
Language	English
Publishing date	2023-09-04
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.30.555522
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Article ; Online: Organelle tethering, pore formation and SNARE compensation in the late endocytic pathway.

Davis, Luther J / Bright, Nicholas A / Edgar, James R / Parkinson, Michael D J / Wartosch, Lena / Mantell, Judith / Peden, Andrew A / Luzio, J Paul

Journal of cell science

2021 Volume 134, Issue 10

Abstract: To provide insights into the kiss-and-run and full fusion events resulting in endocytic delivery to lysosomes, we investigated conditions causing increased tethering and pore formation between late endocytic organelles in HeLa cells. Knockout of the ... ...

Abstract	To provide insights into the kiss-and-run and full fusion events resulting in endocytic delivery to lysosomes, we investigated conditions causing increased tethering and pore formation between late endocytic organelles in HeLa cells. Knockout of the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) VAMP7 and VAMP8 showed, by electron microscopy, the accumulation of tethered lysosome-associated membrane protein (LAMP)-carrier vesicles around multivesicular bodies, as well as the appearance of 'hourglass' profiles of late endocytic organelles attached by filamentous tethers, but did not prevent endocytic delivery to lysosomal hydrolases. Subsequent depletion of the SNARE YKT6 reduced this delivery, consistent with it compensating for the absence of VAMP7 and VAMP8. We also investigated filamentous tethering between multivesicular bodies and enlarged endolysosomes following depletion of charged multi-vesicular body protein 6 (CHMP6), and provide the first evidence that pore formation commences at the edge of tether arrays, with pore expansion required for full membrane fusion.
MeSH term(s)	Endosomes ; HeLa Cells ; Humans ; Lysosomes ; Membrane Fusion ; R-SNARE Proteins/genetics ; SNARE Proteins/genetics
Chemical Substances	R-SNARE Proteins ; SNARE Proteins ; VAMP7 protein, human ; VAMP8 protein, human ; YKT6 protein, human
Language	English
Publishing date	2021-05-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.255463
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Article ; Online: Tetherin antagonism by SARS-CoV-2 ORF3a and spike protein enhances virus release.

Stewart, Hazel / Palmulli, Roberta / Johansen, Kristoffer H / McGovern, Naomi / Shehata, Ola M / Carnell, George W / Jackson, Hannah K / Lee, Jin S / Brown, Jonathan C / Burgoyne, Thomas / Heeney, Jonathan L / Okkenhaug, Klaus / Firth, Andrew E / Peden, Andrew A / Edgar, James R

EMBO reports

2023 Volume 24, Issue 12, Page(s) e57224

Abstract: The antiviral restriction factor, tetherin, blocks the release of several different families of enveloped viruses, including the Coronaviridae. Tetherin is an interferon-induced protein that forms parallel homodimers between the host cell and viral ... ...

Abstract	The antiviral restriction factor, tetherin, blocks the release of several different families of enveloped viruses, including the Coronaviridae. Tetherin is an interferon-induced protein that forms parallel homodimers between the host cell and viral particles, linking viruses to the surface of infected cells and inhibiting their release. We demonstrate that SARS-CoV-2 infection causes tetherin downregulation and that tetherin depletion from cells enhances SARS-CoV-2 viral titres. We investigate the potential viral proteins involved in abrogating tetherin function and find that SARS-CoV-2 ORF3a reduces tetherin localisation within biosynthetic organelles where Coronaviruses bud, and increases tetherin localisation to late endocytic organelles via reduced retrograde recycling. We also find that expression of Spike protein causes a reduction in cellular tetherin levels. Our results confirm that tetherin acts as a host restriction factor for SARS-CoV-2 and highlight the multiple distinct mechanisms by which SARS-CoV-2 subverts tetherin function.
MeSH term(s)	Humans ; Bone Marrow Stromal Antigen 2/antagonists & inhibitors ; Bone Marrow Stromal Antigen 2/metabolism ; COVID-19/virology ; GPI-Linked Proteins/genetics ; GPI-Linked Proteins/metabolism ; SARS-CoV-2/physiology ; Spike Glycoprotein, Coronavirus/genetics ; Virus Release
Chemical Substances	Bone Marrow Stromal Antigen 2 ; GPI-Linked Proteins ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; ORF3a protein, SARS-CoV-2
Language	English
Publishing date	2023-10-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.15252/embr.202357224
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Zs.A 5433: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Multi-omic approach characterises the neuroprotective role of retromer in regulating lysosomal health.

Daly, James L / Danson, Chris M / Lewis, Philip A / Zhao, Lu / Riccardo, Sara / Di Filippo, Lucio / Cacchiarelli, Davide / Lee, Daehoon / Cross, Stephen J / Heesom, Kate J / Xiong, Wen-Cheng / Ballabio, Andrea / Edgar, James R / Cullen, Peter J

Nature communications

2023 Volume 14, Issue 1, Page(s) 3086

Abstract: Retromer controls cellular homeostasis through regulating integral membrane protein sorting and transport and by controlling maturation of the endo-lysosomal network. Retromer dysfunction, which is linked to neurodegenerative disorders including ... ...

Abstract	Retromer controls cellular homeostasis through regulating integral membrane protein sorting and transport and by controlling maturation of the endo-lysosomal network. Retromer dysfunction, which is linked to neurodegenerative disorders including Parkinson's and Alzheimer's diseases, manifests in complex cellular phenotypes, though the precise nature of this dysfunction, and its relation to neurodegeneration, remain unclear. Here, we perform an integrated multi-omics approach to provide precise insight into the impact of Retromer dysfunction on endo-lysosomal health and homeostasis within a human neuroglioma cell model. We quantify widespread changes to the lysosomal proteome, indicative of broad lysosomal dysfunction and inefficient autophagic lysosome reformation, coupled with a reconfigured cell surface proteome and secretome reflective of increased lysosomal exocytosis. Through this global proteomic approach and parallel transcriptomic analysis, we provide a holistic view of Retromer function in regulating lysosomal homeostasis and emphasise its role in neuroprotection.
MeSH term(s)	Humans ; Neuroprotection ; Multiomics ; Proteome/metabolism ; Proteomics ; Endosomes/metabolism ; Protein Transport/physiology ; Lysosomes/metabolism
Chemical Substances	Proteome
Language	English
Publishing date	2023-05-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-38719-8
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Article ; Online: Ultrastructural insight into SARS-CoV-2 entry and budding in human airway epithelium.

Pinto, Andreia L / Rai, Ranjit K / Brown, Jonathan C / Griffin, Paul / Edgar, James R / Shah, Anand / Singanayagam, Aran / Hogg, Claire / Barclay, Wendy S / Futter, Clare E / Burgoyne, Thomas

Nature communications

2022 Volume 13, Issue 1, Page(s) 1609

Abstract: Ultrastructural studies of SARS-CoV-2 infected cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Here, we examined human airway epithelium infected with three different isolates of SARS-CoV-2 including ... ...

Abstract	Ultrastructural studies of SARS-CoV-2 infected cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Here, we examined human airway epithelium infected with three different isolates of SARS-CoV-2 including the B.1.1.7 variant by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Key SARS-CoV-2 entry molecules, ACE2 and TMPRSS2, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistently, extracellular virions were seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion where tomography showed that the viral membrane was continuous with the apical plasma membrane and the nucleocapsids diluted, compared with unfused virus, demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein. Tomography showed concentration of nucleocapsids round the periphery of profiles strongly suggestive of viral budding into these compartments and this may explain how virions gain their S glycoprotein containing envelope.
MeSH term(s)	COVID-19 ; Epithelium/metabolism ; Humans ; Peptidyl-Dipeptidase A/metabolism ; SARS-CoV-2
Chemical Substances	Peptidyl-Dipeptidase A (EC 3.4.15.1)
Language	English
Publishing date	2022-03-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-29255-y
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Article ; Online: OPTN recruitment to a Golgi-proximal compartment regulates immune signalling and cytokine secretion.

O'Loughlin, Thomas / Kruppa, Antonina J / Ribeiro, Andre L R / Edgar, James R / Ghannam, Abdulaziz / Smith, Andrew M / Buss, Folma

Journal of cell science

2020 Volume 133, Issue 12

Abstract: Optineurin (OPTN) is a multifunctional protein involved in autophagy and secretion, as well as nuclear factor κB (NF-κB) and IRF3 signalling, ... ...

Abstract	Optineurin (OPTN) is a multifunctional protein involved in autophagy and secretion, as well as nuclear factor κB (NF-κB) and IRF3 signalling, and
MeSH term(s)	Cell Cycle Proteins ; Cytokines/genetics ; Glaucoma, Open-Angle ; Humans ; Membrane Transport Proteins ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Protein Transport ; Signal Transduction ; Transcription Factor TFIIIA/genetics ; Transcription Factor TFIIIA/metabolism
Chemical Substances	Cell Cycle Proteins ; Cytokines ; Membrane Transport Proteins ; NF-kappa B ; OPTN protein, human ; Transcription Factor TFIIIA
Language	English
Publishing date	2020-06-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.239822
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