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The EMBO Journal Oct 2014The last decade has been marked by tremendous progress in our understanding of the cell biology of mitochondria, with the identification of molecules and mechanisms that... (Review)
Review
The last decade has been marked by tremendous progress in our understanding of the cell biology of mitochondria, with the identification of molecules and mechanisms that regulate their fusion, fission, motility, and the architectural transitions within the inner membrane. More importantly, the manipulation of these machineries in tissues has provided links between mitochondrial dynamics and physiology. Indeed, just as the proteins required for fusion and fission were identified, they were quickly linked to both rare and common human diseases. This highlighted the critical importance of this emerging field to medicine, with new hopes of finding drugable targets for numerous pathologies, from neurodegenerative diseases to inflammation and cancer. In the midst of these exciting new discoveries, an unexpected new aspect of mitochondrial cell biology has been uncovered; the generation of small vesicular carriers that transport mitochondrial proteins and lipids to other intracellular organelles. These mitochondrial-derived vesicles (MDVs) were first found to transport a mitochondrial outer membrane protein MAPL to a subpopulation of peroxisomes. However, other MDVs did not target peroxisomes and instead fused with the late endosome, or multivesicular body. The Parkinson's disease-associated proteins Vps35, Parkin, and PINK1 are involved in the biogenesis of a subset of these MDVs, linking this novel trafficking pathway to human disease. In this review, we outline what has been learned about the mechanisms and functional importance of MDV transport and speculate on the greater impact of these pathways in cellular physiology.
Topics: Animals; Humans; Mitochondria; Mitochondrial Proteins; Organelles; Transport Vesicles
PubMed: 25107473
DOI: 10.15252/embj.201488104 -
The FEBS Journal Jan 2021The Rab family of small GTPases regulates intracellular membrane trafficking by orchestrating the biogenesis, transport, tethering, and fusion of membrane-bound... (Review)
Review
The Rab family of small GTPases regulates intracellular membrane trafficking by orchestrating the biogenesis, transport, tethering, and fusion of membrane-bound organelles and vesicles. Like other small GTPases, Rabs cycle between two states, an active (GTP-loaded) state and an inactive (GDP-loaded) state, and their cycling is catalyzed by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Because an active form of each Rab localizes on a specific organelle (or vesicle) and recruits various effector proteins to facilitate each step of membrane trafficking, knowing when and where Rabs are activated and what effectors Rabs recruit is crucial to understand their functions. Since the discovery of Rabs, they have been regarded as one of the central hubs for membrane trafficking, and numerous biochemical and genetic studies have revealed the mechanisms of Rab functions in recent years. The results of these studies have included the identification and characterization of novel GEFs, GAPs, and effectors, as well as post-translational modifications, for example, phosphorylation, of Rabs. Rab functions beyond the simple effector-recruiting model are also emerging. Furthermore, the recently developed CRISPR/Cas technology has enabled acceleration of knockout analyses in both animals and cultured cells and revealed previously unknown physiological roles of many Rabs. In this review article, we provide the most up-to-date and comprehensive lists of GEFs, GAPs, effectors, and knockout phenotypes of mammalian Rabs and discuss recent findings in regard to their regulation and functions.
Topics: Animals; Biological Transport; Eukaryotic Cells; GTPase-Activating Proteins; Guanine Nucleotide Exchange Factors; Guanosine Diphosphate; Guanosine Triphosphate; Humans; Organelles; Phosphorylation; Phylogeny; Protein Processing, Post-Translational; Saccharomyces cerevisiae; Terminology as Topic; Transport Vesicles; rab GTP-Binding Proteins
PubMed: 32542850
DOI: 10.1111/febs.15453 -
Cell May 2015Most cancer cells release heterogeneous populations of extracellular vesicles (EVs) containing proteins, lipids, and nucleic acids. In vitro experiments showed that EV...
Most cancer cells release heterogeneous populations of extracellular vesicles (EVs) containing proteins, lipids, and nucleic acids. In vitro experiments showed that EV uptake can lead to transfer of functional mRNA and altered cellular behavior. However, similar in vivo experiments remain challenging because cells that take up EVs cannot be discriminated from non-EV-receiving cells. Here, we used the Cre-LoxP system to directly identify tumor cells that take up EVs in vivo. We show that EVs released by malignant tumor cells are taken up by less malignant tumor cells located within the same and within distant tumors and that these EVs carry mRNAs involved in migration and metastasis. By intravital imaging, we show that the less malignant tumor cells that take up EVs display enhanced migratory behavior and metastatic capacity. We postulate that tumor cells locally and systemically share molecules carried by EVs in vivo and that this affects cellular behavior.
Topics: Animals; Cell Line, Tumor; Humans; Integrases; Mice; Neoplasm Metastasis; Neoplastic Cells, Circulating; Transport Vesicles
PubMed: 26000481
DOI: 10.1016/j.cell.2015.04.042 -
Current Opinion in Structural Biology Aug 2022Clathrin-mediated endocytosis enables selective uptake of molecules into cells in response to changing cellular needs. It occurs through assembly of coat components... (Review)
Review
Clathrin-mediated endocytosis enables selective uptake of molecules into cells in response to changing cellular needs. It occurs through assembly of coat components around the plasma membrane that determine vesicle contents and facilitate membrane bending to form a clathrin-coated transport vesicle. In this review we discuss recent cryo-electron microscopy structures that have captured a series of events in the life cycle of a clathrin-coated vesicle. Both single particle analysis and tomography approaches have revealed details of the clathrin lattice structure itself, how AP2 may interface with clathrin within a coated vesicle and the importance of PIP2 binding for assembly of the yeast adaptors Sla2 and Ent1 on the membrane. Within cells, cryo-electron tomography of clathrin in flat lattices and high-speed AFM studies provided new insights into how clathrin morphology can adapt during CCV formation. Thus, key mechanical processes driving clathrin-mediated endocytosis have been captured through multiple techniques working in partnership.
Topics: Cell Membrane; Clathrin; Clathrin-Coated Vesicles; Coated Vesicles; Cryoelectron Microscopy; Endocytosis; Saccharomyces cerevisiae
PubMed: 35872561
DOI: 10.1016/j.sbi.2022.102427 -
Traffic (Copenhagen, Denmark) Jul 2012The conserved oligomeric Golgi (COG) complex co-ordinates retrograde vesicle transport within the Golgi. These vesicles maintain the distribution of glycosylation... (Review)
Review
The conserved oligomeric Golgi (COG) complex co-ordinates retrograde vesicle transport within the Golgi. These vesicles maintain the distribution of glycosylation enzymes between the Golgi's cisternae, and therefore COG is intimately involved in glycosylation homeostasis. Recent years have greatly enhanced our knowledge of COG's composition, protein interactions, cellular function and most recently also its structure. The emergence of COG-dependent human glycosylation disorders gives particular relevance to these advances. The structural data have firmly placed COG in the family of multi-subunit tethering complexes that it shares with the exocyst, Dsl1 and Golgi-associated retrograde protein (GARP) complexes. Here, we review our knowledge of COG's involvement in vesicle tethering at the Golgi. In particular, we consider what this knowledge may add to our molecular understanding of vesicle tethering and how it impacts on the fine tuning of Golgi function, most notably glycosylation.
Topics: Animals; Congenital Disorders of Glycosylation; Glycosylation; Golgi Apparatus; Humans; Protein Processing, Post-Translational; Transport Vesicles; Vesicular Transport Proteins
PubMed: 22300173
DOI: 10.1111/j.1600-0854.2012.01338.x -
Methods in Molecular Biology (Clifton,... 2015Rab proteins represent the largest branch of the Ras-like small GTPase superfamily and there are 66 Rab genes in the human genome. They alternate between GTP- and... (Review)
Review
Rab proteins represent the largest branch of the Ras-like small GTPase superfamily and there are 66 Rab genes in the human genome. They alternate between GTP- and GDP-bound states, which are facilitated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and function as molecular switches in regulation of intracellular membrane trafficking in all eukaryotic cells. Each Rab targets to an organelle and specify a transport step along exocytic, endocytic, and recycling pathways as well as the crosstalk between these pathways. Through interactions with multiple effectors temporally, a Rab can control membrane budding and formation of transport vesicles, vesicle movement along cytoskeleton, and membrane fusion at the target compartment. The large number of Rab proteins reflects the complexity of the intracellular transport system, which is essential for the localization and function of membrane and secretory proteins such as hormones, growth factors, and their membrane receptors. As such, Rab proteins have emerged as important regulators for signal transduction, cell growth, and differentiation. Altered Rab expression and/or activity have been implicated in diseases ranging from neurological disorders, diabetes to cancer.
Topics: Animals; Biological Transport; Humans; Transport Vesicles; rab GTP-Binding Proteins
PubMed: 25800828
DOI: 10.1007/978-1-4939-2569-8_1 -
The Journal of Cell Biology Mar 2019Palade's corpus placed small vesicles as the sole means to transport proteins across stable distinct compartments of the secretory pathway. We suggest that cargo,... (Review)
Review
Palade's corpus placed small vesicles as the sole means to transport proteins across stable distinct compartments of the secretory pathway. We suggest that cargo, spatial organization of secretory compartments, and the timing of fission of cargo-filled containers dictate the design of transport intermediates that can be vesicles and transient direct tunnels.
Topics: Animals; Golgi Apparatus; Humans; Protein Transport; Secretory Pathway; Transport Vesicles
PubMed: 30718263
DOI: 10.1083/jcb.201811073 -
Frontiers in Immunology 2020is the causative agent of a severe pneumonia called Legionnaires' disease. The environmental bacterium replicates in free-living amoebae as well as in lung macrophages... (Review)
Review
is the causative agent of a severe pneumonia called Legionnaires' disease. The environmental bacterium replicates in free-living amoebae as well as in lung macrophages in a distinct compartment, the -containing vacuole (LCV). The LCV communicates with a number of cellular vesicle trafficking pathways and is formed by a plethora of secreted bacterial effector proteins, which target host cell proteins and lipids. Phosphoinositide (PI) lipids are pivotal determinants of organelle identity, membrane dynamics and vesicle trafficking. Accordingly, eukaryotic cells tightly regulate the production, turnover, interconversion, and localization of PI lipids. modulates the PI pattern in infected cells for its own benefit by (i) recruiting PI-decorated vesicles, (ii) producing effectors acting as PI interactors, phosphatases, kinases or phospholipases, and (iii) subverting host PI metabolizing enzymes. The PI conversion from PtdIns(3) to PtdIns(4) represents a decisive step during LCV maturation. In this review, we summarize recent progress on elucidating the strategies, by which subverts host PI lipids to promote LCV formation and intracellular replication.
Topics: Bacterial Proteins; Cell Membrane; Endoplasmic Reticulum; Host-Pathogen Interactions; Humans; Legionella pneumophila; Legionnaires' Disease; Macrophages; Phosphatidylinositols; Secretory Vesicles; Transport Vesicles; Vacuoles
PubMed: 32117224
DOI: 10.3389/fimmu.2020.00025 -
Journal of Biosciences 2022Eukaryotic cells use small membrane-enclosed vesicles to transport molecular cargo between intracellular compartments. Interactions between molecules on vesicles and...
Eukaryotic cells use small membrane-enclosed vesicles to transport molecular cargo between intracellular compartments. Interactions between molecules on vesicles and compartments determine the source and target compartment of each vesicle type. The set of compartment and vesicle types in a cell define the nodes and edges of a transport graph known as the vesicle traffic network. The transmembrane SNARE proteins that regulate vesicle fusion to target compartments travel in cycles through the transport graph, but the paths they follow must be tightly regulated to avoid aberrant vesicle fusion. Here we use graph-theoretic ideas to understand how such molecular constraints place constraints on the structure of the transport graph. We identify edge connectivity (the minimum number of edges that must be removed to disconnect a graph) as a key determinant that separates allowed and disallowed types of transport graphs. As we increase the flexibility of molecular regulation, the required edge connectivity decreases, so more types of vesicle transport graphs are allowed. These results can be used to aid the discovery of new modes of molecular regulation and new vesicle traffic pathways.
Topics: Computational Biology; Computer Graphics; Eukaryotic Cells; SNARE Proteins; Transport Vesicles
PubMed: 35092413
DOI: No ID Found -
The Journal of Cell Biology Dec 2016Protein traffic is of critical importance for normal cellular physiology. In eukaryotes, spherical transport vesicles move proteins and lipids from one internal... (Review)
Review
Protein traffic is of critical importance for normal cellular physiology. In eukaryotes, spherical transport vesicles move proteins and lipids from one internal membrane-bound compartment to another within the secretory pathway. The process of directing each individual protein to a specific destination (known as protein sorting) is a crucial event that is intrinsically linked to vesicle biogenesis. In this review, we summarize the principles of cargo sorting by the vesicle traffic machinery and consider the diverse mechanisms by which cargo proteins are selected and captured into different transport vesicles. We focus on the first two compartments of the secretory pathway: the endoplasmic reticulum and Golgi. We provide an overview of the complexity and diversity of cargo adaptor function and regulation, focusing on recent mechanistic discoveries that have revealed insight into protein sorting in cells.
Topics: Animals; Endoplasmic Reticulum; Golgi Apparatus; Humans; Models, Biological; Protein Transport; Transport Vesicles
PubMed: 27903609
DOI: 10.1083/jcb.201610031