Exosome secretion of dendritic cells is regulated by Hrs, an ESCRT-0 protein

Tamai, Keiichi; Tanaka, Nobuyuki; Nakano, Takashi; Kakazu, Eiji; Kondo, Yasuteru; Inoue, Jun; Shiina, Masaaki; Fukushima, Koji; Hoshino, Tomoaki; Sano, Kohei; Ueno, Yoshiyuki; Shimosegawa, Tooru; Sugamura, Kazuo

doi:10.1016/j.bbrc.2010.07.083

Cited by 223 publications

(184 citation statements)

References 29 publications

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“…Whereas ESCRT-independent mechanisms are involved in MVB and exosome biogenesis (Trajkovic et al, 2008;van Niel et al, 2011), our observations and recent reports (Baietti et al, 2012;Tamai et al, 2010) show that the formation and secretion of a population of exosomes also rely on the function of ESCRTs and accessory proteins, and that only selected components may be involved in protein sorting and the formation of the ILVs fated to be secreted as exosomes. These observations will certainly contribute to our understanding of the mechanisms involved in exosome formation and will open an avenue for modulating the nature of exosomes and their composition.…”

Section: Discussionsupporting

confidence: 64%

“…It has also been reported that the ESCRT-0 component HRS could be required for exosome formation and/or secretion by dendritic cells (DCs), and thereby impact on their antigen-presenting capacity (Tamai et al, 2010). The transferrin receptor (TfR) in reticulocytes that is generally fated for exosome secretion, although not ubiquitylated, interacts with ALIX for MVB sorting (Géminard et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles

Colombo

Moita

Niel

et al. 2013

Journal of Cell Science

1,079

1,109

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SummaryExosomes are extracellular vesicles (EVs) secreted upon fusion of endosomal multivesicular bodies (MVBs) with the plasma membrane. The mechanisms involved in their biogenesis have not yet been fully identified although they could be used to modulate exosome formation and therefore are a promising tool in understanding exosome functions. We have performed an RNA interference screen targeting 23 components of the endosomal sorting complex required for transport (ESCRT) machinery and associated proteins in MHC class II (MHC II)-expressing HeLa-CIITA cells. Silencing of HRS, STAM1 or TSG101 reduced the secretion of EV-associated CD63 and MHC II but each gene altered differently the size and/or protein composition of secreted EVs, as quantified by immuno-electron microscopy. By contrast, depletion of VPS4B augmented this secretion while not altering the features of EVs. For several other ESCRT subunits, it was not possible to draw any conclusions about their involvement in exosome biogenesis from the screen. Interestingly, silencing of ALIX increased MHC II exosomal secretion, as a result of an overall increase in intracellular MHC II protein and mRNA levels. In human dendritic cells (DCs), ALIX depletion also increased MHC II in the cells, but not in the released CD63-positive EVs. Such differences could be attributed to a greater heterogeneity in size, and higher MHC II and lower CD63 levels in vesicles recovered from DCs as compared with HeLa-CIITA. The results reveal a role for selected ESCRT components and accessory proteins in exosome secretion and composition by HeLa-CIITA. They also highlight biogenetic differences in vesicles secreted by a tumour cell line and primary DCs.

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Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles

Colombo

Moita

Niel

et al. 2013

Journal of Cell Science

1,079

1,109

View full text Add to dashboard Cite

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“…Mutations in these motifs impair the secretion of SIMPLE to exosomes, altering MVBs biogenesis [49]. Moreover, Hrs conditional knock-out (KO) in dendritic cells (DC) significantly reduces exosome release, pointing to an important role for ESCRT components in exosome secretion [50].…”

Section: Escrt-dependent and Independent Sorting Mechanisms Into Ilvsmentioning

confidence: 99%

Post-translational add-ons mark the path in exosomal protein sorting

Moreno-Gonzalo

Fernández-Delgado

Sánchez‐Madrid

2017

Cell. Mol. Life Sci.

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“…Later, this machinery was implicated in other two key functions: budding of retrovirus (Demirov et al, 2002;Garrus et al, 2001;Martin-Serrano et al, 2001;Patnaik et al, 2000;VerPlank et al, 2001) and membrane scission at ending stages of cytokinesis (Carlton and Martin-Serrano, 2007). Only more recently, the ESCRTs were reported be involved in the biogenesis of exosomes and microvesicles (Gross et al, 2012;Tamai et al, 2010). The ESCRT machinery is composed of approximately thirty proteins that assemble into four complexes, denominated: ESCRT-0, ESCRT-I, ESCRT-II e ESCRT-III.…”

Section: Exosome Biogenesis: Membrane Bending and Cargo Recruitment Tmentioning

confidence: 99%

Estudo da função de AP1y2 e Alix no direcionamento de proteínas para degradação em lisossomos ou liberação em vesículas extracelulares

Januário¹

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Several proteins regulate the targeting of cargo to MVBs. Studies that delineated the functions of AP1 in protein trafficking, focused on complexes containing the γ1 subunit, which mediates transport between trans-Golgi network (TGN) and endosomes. However, the human genome encodes a second isoform of this subunit, named γ2. Evidences from the literature, as well as results from our research group, indicate that AP1γ2 regulates transport pathways that are distinct from the pathways classically attributed to AP1. By performing EGF-uptake assays under γ1 or γ2 knockdown (KD) conditions, it was observed that γ2 is required for degradation of internalized EGF, effect also observed for the EGF receptor (EGFR) using cell surface biotinylation assays. These results demonstrate that the lysosomal degradation of the EGF-EGFR complexes via the canonical MVBs pathway requires the AP1γ2 complex, but not AP1γ1. In parallel with this study, we also analyzed the molecular mechanism of HIV-1 Nef targeting to MVBs associated with the EVs release. Nef is an important determinant in the modulation of the intracellular environment for efficient HIV replication and progression to AIDS. Nef is actively secreted via EVs and its release may lead to apoptosis of bystander acceptor cells. Moreover, Nef reduces the levels of CD4 and MHC-I molecules in EVs. Despite the importance of Nef release in EVs, the molecular mechanism used by Nef to be exported via (Fig. 1).Cada complexo AP é um heterotetrâmero, ou seja, cada complexo é formado por quatro subunidades distintas. Eles são constituídos por duas subunidades grandes de aproximadamente 100 kDa, as subunidades γ e β1 no complexo AP1, sendo a subunidade γ homóloga às subunidades α, δ, ε e ζ de AP2, AP3, AP4 e AP5, respectivamente, e a subunidade β1 homóloga às subunidades β2, β3, β4 e β5 de AP2, AP3, AP4 e AP5, respectivamente. Também possuem uma subunidade média de aproximadamente 50 kDa (μ1, μ2, μ3, μ4 e μ5 em AP1 a AP5, respectivamente) e uma subunidade pequena de aproximadamente 20 kDa (σ1, σ2, σ3, σ4 e σ5 em AP1 a AP5) (Paczkowski, Richardson and Fromme 2015, Robinson 2015) (Fig. 1). É importante ressaltar que cada uma das subunidades tem importantes funções moleculares que O esquema representa a estrutura e as vias clássicas de funcionamento dos componentes da família de proteínas adaptadoras, os heterotetrâmeros AP1 à AP5 e suas subunidades. Cada complexo AP é formado por duas subunidades grandes (γ e β1 em AP1, sendo a subunidade γ homóloga às subunidades α, δ, ε e ζ de AP2, AP3, AP4 e AP5, respectivamente. E a subunidade β1 homóloga a β2, β3, β4 e β5 de AP2, AP3, AP4 e AP5, respectivamente. Os APs são formados ainda por uma subunidade média (μ1, μ2, μ3, μ4 e μ5 em AP1 a AP5, respectivamente) e uma subunidade pequena (σ1, σ2, σ3, σ4 e σ5 em AP1 a AP5) (Hirst et al. 2011, Boehm & Bonifacino 2001. Os complexos adaptadores AP1, AP2 e AP3 apresentam distintas isoformas descritas de suas subunidades codificadas por diferentes genes. AP1 possui isoformas da subunidade γ (γ1 e γ2), d...

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Exosome secretion of dendritic cells is regulated by Hrs, an ESCRT-0 protein

Cited by 223 publications

References 29 publications

Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles

Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles

Post-translational add-ons mark the path in exosomal protein sorting

Estudo da função de AP1y2 e Alix no direcionamento de proteínas para degradação em lisossomos ou liberação em vesículas extracelulares

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