Protein sorting into multivesicular endosomes

Raiborg, Camilla; Rusten, Tor Erik; Stenmark, Harald

doi:10.1016/s0955-0674(03)00080-2

Cited by 451 publications

(446 citation statements)

References 68 publications

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“…CD63 is found in MVB, ILV and hence in exosomes; this protein and its chimeras (GFP-CD63) are used as reporters for MVB/exosomes, 2,8,14 and allow quantitation of exosome secretion. 9,71 Western blot analysis of endogenous or chimeric CD63 in isolated exosomes is used to measure exosomes, 9 as the signal correlates with nanoparticle concentration data (nanoparticles/ml) as confirmed by Nanopaticle Tracking Analysis (NTA) 72,73 (Supplementary Figure S2).…”

Section: Methodsmentioning

confidence: 99%

“…1 ILVs are generated by inward budding of late endosome limiting membrane in a precisely regulated maturation process. 2,3 Two main pathways are involved in MVB maturation. 4,5 In addition to the ESCRT (endosomal complex required for traffic) proteins, 6 there is increasing evidence that lipids such as lyso-bisphosphatidic acid (LBPA), 7 ceramides 8 and diacylglycerol (DAG) 9 contribute to this membrane invagination process.…”

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confidence: 99%

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Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

et al. 2015

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Multivesicular bodies (MVBs) are endocytic compartments that enclose intraluminal vesicles (ILVs) formed by inward budding from the limiting membrane of endosomes. In T lymphocytes, these ILV contain Fas ligand (FasL) and are secreted as 'lethal exosomes' following activation-induced fusion of the MVB with the plasma membrane. Diacylglycerol (DAG) and diacylglycerol kinase α (DGKα) regulate MVB maturation and polarized traffic, as well as subsequent secretion of pro-apoptotic exosomes, but the molecular basis underlying these phenomena remains unclear. Here we identify protein kinase D (PKD) family members as DAG effectors involved in MVB genesis and secretion. We show that the inducible secretion of exosomes is enhanced when a constitutively active PKD1 mutant is expressed in T lymphocytes, whereas exosome secretion is impaired in PKD2-deficient mouse T lymphoblasts and in PKD1/3-null B cells. Analysis of PKD2-deficient T lymphoblasts showed the presence of large, immature MVB-like vesicles and demonstrated defects in cytotoxic activity and in activation-induced cell death. Using pharmacological and genetic tools, we show that DGKα regulates PKD1/2 subcellular localization and activation. Our studies demonstrate that PKD1/2 is a key regulator of MVB maturation and exosome secretion, and constitutes a mediator of the DGKα effect on MVB secretory traffic. Exosomes are nanovesicles that form as intraluminal vesicles (ILVs) inside multivesicular bodies (MVBs) and are then secreted by numerous cell types. 1 ILVs are generated by inward budding of late endosome limiting membrane in a precisely regulated maturation process. 2,3 Two main pathways are involved in MVB maturation. 4,5 In addition to the ESCRT (endosomal complex required for traffic) proteins, 6 there is increasing evidence that lipids such as lyso-bisphosphatidic acid (LBPA), 7 ceramides 8 and diacylglycerol (DAG) 9 contribute to this membrane invagination process.Exosomes participate in many biological processes related to T-cell receptor (TCR)-triggered immune responses, including T lymphocyte-mediated cytotoxicity and activationinduced cell death (AICD), antigen presentation and intercellular miRNA exchange. [10][11][12][13][14][15] The discovery of exosome involvement in these responses increased interest in the regulation of exosome biogenesis and secretory traffic, with special attention to the contribution of lipids such as ceramide and DAG, as well as DAG-binding proteins. 14,16-21 These studies suggest that positive and negative DAG regulators may control secretory traffic. By transforming DAG into phosphatidic acid (PA), diacylglycerol kinase α (DGKα) is essential for the negative control of DAG function in T lymphocytes. 22 DGKα translocates transiently to the T-cell membrane after human muscarinic type 1 receptor (HM1R) triggering or to the immune synapse (IS) after TCR stimulation; at these subcellular locations, DGKα acts as a negative modulator of phospholipase C (PLC)-generated DAG. 23,24 The secretory vesicle pathway involves several DAGc...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

et al. 2015

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“…Then ESCRT-III recruits the deubiquitinating enzyme Doa4 which removes the ubiquitin tag from the cargo protein prior to sorting into the MVB vesicles. Finally, a multimeric AAA-type (ATPase associated with various cellular activities) ATPase Vps4 binds to ESCRT -III and disassembles the ESCRT III complex in an ATP-dependent manner [12,13].…”

Section: Sorting Via the Endosomal Sorting Complex Required For Transmentioning

confidence: 99%

Exosomes as intercellular signalosomes and pharmacological effectors

Record

Subra

Silvente-Poirot

et al. 2011

Biochemical Pharmacology

473

336

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International audienceCell secretion is a general process involved in various biological responses. Exosomes are part of this process and have gained considerable scientific interest in the past five years. Several steps through investigations across the last 20years can explain this interest. First characterized during reticulocyte maturation, they were next characterized as a key player in the immune response and cancer immunotherapy. More recently they were characterized as vectors of mRNAs, miRNAs and also lipid mediators able to act on target cells. They are the only type of vesicles released from an intracellular compartment from cells in viable conditions. They appear as a vectorized signaling system operating from inside a donor cell towards either the periphery, the cytosol, or possibly to the nucleus of target cells. Exosomes from normal cells trigger positive effects, whereas those from pathological ones, such as tumor cells or infected ones may trigger non-positive health effects. Therefore regulating the biogenesis and secretion of exosomes appear as a pharmacological challenge to intervene in various pathophysiologies. Exosome biogenesis and molecular content, interaction with target cells, utilisation as biomarkers, and functional effects in various pathophysiologies are considered in this review

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“…The ubiquitinated RTKs are selectively recognized by proteins of the endocytic pathway that contain ubiquitin-interacting domains (UBA, UIM, UEV and CUE), such as Epsin, Eps15, Stam and Hrs (HGF regulated tyrosine kinase substrate) among others. These endocytic proteins promote the retention of ubiquitinated receptors within clathrin-coated subcompartments of sorting endosomes, and are involved in the recruitment of ESCRT (endosomal sorting complex required for transport) complexes, which leads to the inward vesiculation of ubiquitinated RTKs (reviewed in Raiborg et al, 2003). Consequently, RTKs may no longer signal or be recycled to the cell surface, and end up being degraded in the lysosome (Figure 3).…”

Section: Regulation Of Met Downregulation: Consequence For Oncogenic mentioning

confidence: 99%

From Tpr-Met to Met, tumorigenesis and tubes

2007

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The receptor for hepatocyte growth factor (HGF)/scatter factor (SF), Met, controls a program of invasive epithelial growth through the coordination of cell proliferation and survival, cell migration and epithelial morphogenesis. This process is important during embryogenesis and for organ regeneration in the adult. However, when deregulated the HGF/SF-Met signaling axis contributes to tumorigenesis and metastasis. Studies on the oncogenic activation of the Met receptor have shed light on the molecular mechanisms underlying the oncogenic activation of receptor tyrosine kinase (RTKs). More than a decade ago, work on the Met related oncogene, Tpr-Met, revealed the mechanism for activation of RTK-derived oncogenes generated following chromosomal translocation. More recently, studies on the mechanisms of downregulation of the Met RTK highlight a role for loss of downregulation in RTK oncogenic activation.

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Protein sorting into multivesicular endosomes

Cited by 451 publications

References 68 publications

Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

Exosomes as intercellular signalosomes and pharmacological effectors

From Tpr-Met to Met, tumorigenesis and tubes

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