Endosome maturation

Institute of Biochemistry, ETH Zurich, Switzerland.
The EMBO Journal (Impact Factor: 10.75). 08/2011; 30(17):3481-500. DOI: 10.1038/emboj.2011.286
Source: PubMed

ABSTRACT Being deeply connected to signalling, cell dynamics, growth, regulation, and defence, endocytic processes are linked to almost all aspects of cell life and disease. In this review, we focus on endosomes in the classical endocytic pathway, and on the programme of changes that lead to the formation and maturation of late endosomes/multivesicular bodies. The maturation programme entails a dramatic transformation of these dynamic organelles disconnecting them functionally and spatially from early endosomes and preparing them for their unidirectional role as a feeder pathway to lysosomes.

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    ABSTRACT: During maturation of endosomes, in addition to the decrease in their internal pH and the modifications of their proteins, changes are thought to occur at the level of their lipid membranes. In the present work, we used the recently developed environment-sensitive membrane probe NR12S to monitor in living cells the lipid order changes that accompany the maturation of endosomes. Internalization studies in HeLa cells using two-photon fluorescence microscopy in the presence of endocytosis markers and inhibitors show that the probe is endocytosed through different energy-dependent pathways. While marginal changes in the probe colour occur during the initial steps of endocytosis, dramatic changes in colour are observed in the membranes of late endosomes and lysosomes. This remarkable colour change, which takes place 2 h after initial binding of NR12S to cell plasma membranes, suggests a loss of lipid ordered phase during endosome maturation. This change of lipid phase likely results from the decrease in the cholesterol content and the hydrolysis of sphingomyelin occurring in the membranes of late endosomes and lysosomes. In comparison to the common endocytosis marker FM4-64, NR12S is many-fold brighter, it can monitor in situ changes in the lipid organization of endosome membranes and its fluorescence at the plasma membrane can be selectively switched off by sodium dithionite. The present work proposes thus a new powerful tool for endocytosis research that enables monitoring changes in the lipid composition of endosome membranes.
    RSC Advances 01/2014; 4(17):8481. DOI:10.1039/c3ra47181k · 3.71 Impact Factor
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    ABSTRACT: Microglia are the resident immune cells in the CNS and play diverse roles in the maintenance of CNS homeostasis. Recent studies have shown that microglia continually survey the CNS microenvironment and scavenge cell debris and aberrant proteins by phagocytosis and pinocytosis, and that reactive microglia are capable to present antigens to T cells and initiate immune responses. However, how microglia process the endocytosed contents and evoke an immune response remain unclear. Here we report that a size-dependent selective transport of small soluble contents from the pinosomal lumen into lysosomes is critical for the antigen processing in microglia. Using fluorescent probes and water-soluble magnetic nanobeads of defined sizes, we showed in cultured rodent microglia, and in a cell-free reconstructed system that pinocytosed proteins become degraded immediately following pinocytosis and the resulting peptides are selectively delivered to major histocompatibility complex class II (MHC-II) containing lysosomes, whereas undegraded proteins are retained in the pinosomal lumen. This early size-based sorting of pinosomal contents relied on the formation of transient tunnel between pinosomes and lysosomes in a Rab7- and dynamin II-dependent manner, which allowed the small contents to pass through but restricted large ones. Inhibition of the size-based sorting markedly reduced proliferation and cytokine release of cocultured CD4(+) T cells, indicating that the size-based sorting is required for efficient antigen presentation by microglial cells. Together, these findings reveal a novel early sorting mechanism for pinosomal luminal contents in microglial cells, which may explain how microglia efficiently process protein antigens and evoke an immune response. Copyright © 2015 the authors 0270-6474/15/352674-15$15.00/0.
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    ABSTRACT: The tumour suppressor gene lethal (2) giant discs (lgd) is involved in endosomal trafficking of transmembrane proteins in Drosophila. Loss of function results in the ligand-independent activation of the Notch pathway in all imaginal disc cells and follicle cells. Analysis of lgd loss of function has largely been restricted to imaginal discs and suggests that no other signalling pathway is affected. The devotion of Lgd to the Notch pathway was puzzling given that lgd loss of function also affects trafficking of components of other signalling pathways, such as the Dpp (a Drosophila BMP) pathway. Moreover, Lgd physically interacts with Shrub, a fundamental component of the ESCRT trafficking machinery, whose loss of function results in the activation of several signalling pathways. Here, we show that during oogenesis lgd loss of function causes ectopic activation of the Drosophila BMP signalling pathway. This activation occurs in somatic follicle cells as well as in germline cells. The activation in germline cells causes an extra round of division, producing egg chambers with 32 instead of 16 cells. Moreover, more germline stem cells were formed. The lgd mutant cells are defective in endosomal trafficking, causing an accumulation of the type I Dpp receptor Thickveins in maturing endosomes, which probably causes activation of the pathway. Taken together, these results show that lgd loss of function causes various effects among tissues and can lead to the activation of signalling pathways other than Notch. They further show that there is a role for the endosomal pathway during oogenesis. © 2015. Published by The Company of Biologists Ltd.
    Development 04/2015; 142(7):1325-35. DOI:10.1242/dev.112961 · 6.27 Impact Factor

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