UBL3 modification influences protein sorting to small extracellular vesicles

Ageta, Hiroshi; Ageta-Ishihara, Natsumi; Hitachi, Keisuke; Karayel, Özge; Onouchi, Takanori; Yamaguchi, Hisateru; Kahyo, Tomoaki; Hatanaka, Ken; Ikegami, Koji; Yoshioka, Yusuke; Nakamura, Kenji; Kosaka, Nobuyoshi; Nakatani, Masashi; Uezumi, Akiyoshi; Ide, Tomihiko; Tsutsumi, Yutaka; Sugimura, Haruhiko; Kinoshita, Makoto; Ochiya, Takahiro; Mann, Matthias; Setou, Mitsutoshi; Tsuchida, Kunihiro

doi:10.1038/s41467-018-06197-y

Cited by 67 publications

(83 citation statements)

References 36 publications

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“…ESCRT-complex proteins (ubiquitin-tagged) [34] Ubiquitin Binding Proteins (ISG15, UBL3) proteins (ubiquitin-tagged) [35,36] Alix (ESCRT-III associated) proteins (especially receptors; ubiquitin-independent) [37] Alix-Syntenin-Syndecan-complex (Phospholipase D2-ARF6-regulated) proteins (binding to heparanase sulfate) [38] Ndfip1 proteins (Nedd4 family members or WW-tagged) [39,40] sphingosine-1-phosphate and receptor proteins (transferrin receptor, CD63) […”

Section: Cargo Sorting Machinery Reported Cargo Referencesmentioning

confidence: 99%

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Extracellular Vesicles as Delivery Vehicles of Specific Cellular Cargo

Mir

Goettsch

2020

Cells

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Extracellular vesicles (EVs) mediate cell-to-cell communication via the transfer of biomolecules locally and systemically between organs. It has been elucidated that the specific EV cargo load is fundamental for cellular response upon EV delivery. Therefore, revealing the specific molecular machinery that functionally regulates the precise EV cargo intracellularly is of importance in understanding the role of EVs in physiology and pathophysiology and conveying therapeutic use. The purpose of this review is to summarize recent findings on the general rules, as well as specific modulator motifs governing EV cargo loading. Finally, we address available information on potential therapeutic strategies to alter cargo loading.

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Section: Cargo Sorting Machinery Reported Cargo Referencesmentioning

confidence: 99%

“…This ISGylation causes the accumulation and degradation of TSG101, resulting in impaired exosome secretion and potentially, subsequent alterations in EV cargo. In addition, UBL3-modification is involved in the protein sorting process of smaller EVs [36].…”

Section: Pathways Of Protein Sortingmentioning

confidence: 99%

Extracellular Vesicles as Delivery Vehicles of Specific Cellular Cargo

Mir

Goettsch

2020

Cells

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“…With its sensitive and specific detection, we anticipate that the iMAGE platform could be readily expanded to measure other EV surface markers, including established as well as novel EV modifications (e.g., ubiquitination). 45 Its solution-phase magnetic actuation further improves assay performance and eases probe selection (e.g., lowaffinity binders) to identify weak but true interactions, 23 and could be readily integrated with other technologies to facilitate molecular assay development. 46,47 Such studies will not only improve biomarker characterization but also empower new applications.…”

Section: Discussionmentioning

confidence: 99%

Dual-Selective Magnetic Analysis of Extracellular Vesicle Glycans

Wang

Sun

Natalia

et al. 2020

Matter

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Extracellular vesicles (EVs) are emerging circulating biomarkers and contain diverse sugar modifications (glycans) that can mediate disease progression. The analysis of EV glycans, however, is challenging due to technology limitations. We have developed a dedicated platform to directly profile EV glycans in native biofluids. The all-magnetic technology utilizes rationally designed nanoparticles and integrated sensors to specifically measure EV-bound glycans but not that of free-floating proteins. The assay is fast, sensitive, and wash-free, and reveals new clinical signatures to differentiate patient prognosis.

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“…Ageta described that the ubiquitin-like 3 (UBL3)/membraneanchored Ub-fold protein (MUB) UBL3 is necessary for protein sorting in sEVs. In serum sEVs of UBL3 knock-out animals, a strong reduction of the total protein content in vesicles was found when gels were loaded with the same volume of a rat serum derived sEV suspension (Ageta et al, 2018). In a different study in cells transfected with siRNAs targeting TSG101 and Hrs, which are proteins of the ESCRT system, a decrease in the number and the total amount of proteins contained in sEVs was induced (Smith, Jackson, & Schorey, 2015).…”

Section: Sumoylation and Its Effect On Sev Cargomentioning

confidence: 96%

SUMOylation regulates protein cargo in Astrocyte-derived small extracellular vesicles

Fernández¹,

Mendez²,

Santis³

et al. 2020

Preprint

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Recent studies have described a new mechanism of intercellular communication mediated by various types of extracellular vesicles (EVs). In particular, exosomes are small EVs (sEVs) released to the extracellular environment by the fusion of the endosomal pathway-related multivesicular bodies (containing intraluminal vesicles) with the plasma membrane. sEVs contain a molecular cargo consisting of lipids, proteins, and nucleic acids. However, the loading mechanisms for this complex molecular cargo have not yet been completely elucidated. In that line, the post translational modification SUMO (Small Ubiquitin-like Modifier) has been shown to impact the incorporation of select proteins into sEVs. We therefore decided to investigate whether SUMOylation is a mechanism that defines protein loading to sEVs. In order to investigate the role of SUMOylation in cargo loading into sEVs, we utilized astrocytes, an essential cell type of the central nervous system with homeostatic functions, to study the impact of SUMOylation on the protein cargo of sEVs. Following SUMO overexpression, achieved by transfection of SUMO plasmids or experimental conditions that modulate SUMOylation in primary astrocyte cultures, we detected proteins related to cell division, translation, and transcription by mass-spectrometry. In astrocyte cultures treated with the general SUMOylation inhibitor 2-D08 (2′,3′,4′-trihydroxy-flavone, 2-(2,3,4-Trihydroxyphenyl)-4H-1-Benzopyran-4-one) we observed an increase in the number of sEVs and a decreased amount of protein cargo within them. In turn, in astrocytes treated with the stress hormone corticosterone, we found an increase of SUMO-2 conjugated proteins and sEVs from these cells contained an augmented protein cargo. In this case, the proteins detected with mass-spectrometry were mostly proteins related to protein translation. To test whether astrocyte-derived sEVs obtained in these experimental conditions could modulate protein synthesis in target cells, we incubated primary neurons with astrocyte-derived sEVs. sEVs from corticosterone-treated astrocytes stimulated protein synthesis while no difference was found with sEVs derived from 2-D08-treated astrocytes. Our results show that SUMO conjugation plays a fundamental role in defining the protein cargo of sEVs impacting the physiological function of target cells.

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UBL3 modification influences protein sorting to small extracellular vesicles

Cited by 67 publications

References 36 publications

Extracellular Vesicles as Delivery Vehicles of Specific Cellular Cargo

Extracellular Vesicles as Delivery Vehicles of Specific Cellular Cargo

Dual-Selective Magnetic Analysis of Extracellular Vesicle Glycans

SUMOylation regulates protein cargo in Astrocyte-derived small extracellular vesicles

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