Rab gtpases and their effectors in plant endosomal. Pdf rab gtpases as coordinators of vesicle traffic. Rab gtpases are key regulators of membrane trafficking in eukaryotic cells, and regulate multiple steps of intracellular transport by controlling vesicle budding, lipid remodeling, interaction with molecular motors and the cytoskeleton, vesicle tethering and. Rab gtpases control intracellular membrane traffic by recruiting specific effector proteins to restricted membranes in a gtpdependent manner. Functional impairments of rab pathways are associated with diseases, such as immunodeficiencies, cancer and neurological disorders. Small regulatory rab gtpases belong to the group of conserved trafficking proteins that govern membrane traffic in all eukaryotes. A potential novel aspect of rab recruitment has recently been suggested for rab27 55. Merged mass spectrometric analysis from both data sets, related to figures.
Inserts are enlargements of the framed regions in merge panel. Rab gtpases implicated in inherited and acquired disorders. Novel functions for rab gtpases in multiple aspects of. Presynaptic neurotransmitter release is dominated by the synaptic vesicle sv cycle and entails the biogenesis, fusion, recycling, reformation or turnover of synaptic vesicles a process involving bulk movement of membrane and proteins.
Rab proteins are key mediators of vesicle transport. Vesicle trafficking between compartments is essential for cellular function and intercellular communication. Here, we present the first systematic characterization of neuronal expression, subcellular localization, and function of rab gtpases in an organism with a brain. Early stages of functional diversification in the rab gtpase gene. In this video we have discussed the mechanism of vesicle docking and fusion. Rab 1a is localized pregolgi intermediates, and rab. Rab regulation by gefs and gaps during membrane traffic. Here, we present the first systematic characterization of neuronal expression, subcellular localization, and function of rab gtpases. Controlling the location and activation of rab gtpases. Stenmark h 2009 rab gtpases as coordinators of vesicle traffic. Membranous vesicles with characteristic rab gtpaseeffector domains comprise the basic infrastructure of the cellular trafficking machinery. Role of small gtpases in polarized vesicle transport to. By this paradigm, goldenring and collaborators had identified that rab8a and rab10 interact with myosins va, vb, and vc, molecules that form homodimers that bind to actin filaments through their head group and.
Gtp can then be cleaved by the endogenous gtpase activity of the rab to produce the gdpbound form. They are small gtpases comprising more than 70 members in humans and function as regulators of vesicles transport, proteins trafficking, membrane targeting and fusion. Rab gtpases control intracellular vesicle traffic by acting as regulatable switches that recruit effector molecules when in their gtpbound form. Rab11 regulates exocytosis of recycling vesicles at the. Rab gtpases, with the help of their effectors ensure. About europe pmc funders joining europe pmc governance roadmap outreach. Here, we report that ypt6, a rab6 homologue in yeast, resides temporarily at the golgi and dissociates into the cytosol upon arrival of ypt32, another rab. The functions of rab gtpases, as well as other gtpases that regulate membrane traffic e.
However, how exactly rab gtpases themselves act upon membrane tethering processes has remained enigmatic. Structural mechanisms for regulation of membrane traffic. Rab proteins control membrane trafficking by cycling between active gtp. Rab gtpases as coordinators of vesicle traffic nature. Pdf rabmediated vesicle trafficking in cancer researchgate. In this chapter, we will give a brief introduction into rab gtpases and focus on. Rabmediated vesicle trafficking in cancer journal of. Right panel shows a merged image of tfnr staining shown as green. Cytoplasmic control of rab family small gtp embo press. In saccharomyces cerevisiae, 11 rabypt gtpases have been identified and their functions are. Rab gtpases are considered to be master regulators of intracellular. In addition, one rab gtpase can recruit a gef for a second rab gtpase that will subsequently replace the first 3.
Rabgtpases activity is coupled to the activity of guanine nucleotide exchange factors or gefs, and gtpase. We treated the cells with p62 and found that p62positive vesicles could merge with. Roles of rabgaps in regulating autophagy sciencedirect. Membrane trafficking between organelles by vesiculotubular carriers is fundamental to the existence of eukaryotic cells.
It is considered a specialized mode of membrane trafficking that is achieved by docking and fusion of secretory vesicles to the plasma membrane i. The functional coupling between multiple rab gtpases ensures the spatiotemporally coordinated regulation of vesicle traffic. Ungermanncorvet and hops tethering complexes coordinators. Rabs are inactive when bound to gdp and are activated by exchanging gdp for gtp. Little is known about how neurons manage to differentially regulate the release of synaptic vesicles svs and dcvs. A core complex of bbs proteins cooperates with the gtpase rab8 to promote ciliary membrane biogenesis. Pdf integrinmediated function of rab gtpases in cancer. These rab gtpases would be good models for studying how and why plants acquired plantspecific rab gtpases. We focus on the rab enzymes, critical organisers of the trafficking. This led to the idea that rab gtpases proofread the interaction between a vesicle and its target membrane before the membrane fusion reaction and thus act as key regulators of membrane traffic. Rab gtpases are members of the wider ras superfamily and are best known for playing essential roles in exocytic and endocytic membrane trafficking barbero et al. Soon after their discovery three decades ago, it was appreciated that rab gtpases localise to specific membrane domains and organelle membranes within eukaryotic cells. Nephrocytes are highly active in endocytosis and vesicle trafficking. Rab proteins alternate between an activated gtpbound state and an inactivated gdpbound state.
By virtue of prenylation moieties anchored to their cterminus, rabs bind intracellular. Rab gtpases regulate endocytosis by decorating intracellular vesicles and. Rab gap cascade regulates dynamics of ypt6 in the golgi. Source data for figure 1 embr201846794sup0004sdatafig1. Rab protein activity is controlled by cycling between the active gtpbound and inactive gdpbound forms. Pdf a large group of small rab gtpases which mediate secretory and endosomal membrane transport, as well as autophagosome biogenesis, are essential. Secretion is a fundamental biological activity of all eukaryotic cells by which they release certain substances in the extracellular space. Early endosome marker rab5 gtpase, a key member of the rab family, plays a crucial role in endocytosis and. Specific rab protein together with the cognate effectors coordinates the dynamics of trafficking pathway and determines the cargo proteins destination. Rab gtpases ensure specificity and directionality of trafficking steps by regulating the movement of transport carriers along cytoskeletal tracks, and the recruitment of tethering factors required for the docking and fusion processes. Rab gtpases are members of the ras superfamily of small gtpases, and collectively function in regulating the myriad of membrane transport processes in eukaryotic cells 2, 3. Crosstalk between multiple rab gtpases through shared effectors, or through effectors that recruit selective rab activators, ensures the spatiotemporal regulation of vesicle traffic.
Despite their roles in membrane tethering and fusion, several rab gtpases have been implicated in controlling vesicle budding stenmark, 2009. Thousands of rab gtpases for the cell biologist plos. In this cell science at a glance and the accompanying poster, we highlight the regulation of rab gtpases by proteins that control their membrane association and activation state, and provide an overview of the cellular processes. The rab and arf gtpases are members of two of the rasrelated subfamilies that function in regulating vesicle trafficking, starting from regulating the formation of vesicles on donor membranes and directing trafficking specificity to and facilitating vesicle docking on target membranes zerial and mcbride, 2001. They seem to be involved in all aspects of vesicle trafficking. Secretory vesicle traffic is thought to be regulated by a family of rab small gtpases. Investigations of nephrocyte cell biological processes are fundamental to understanding the insect renal system. Request pdf on jan 1, 2018, yuxuan miao and others published collaboration between two distinct rab small gtpase trafficking circuits to mediate bacterial clearance from the. Members of the rab family of small gtpases are key regulators of membrane trafficking involved in transport, tethering and docking of vesicles through their effectors. In this cell science at a glance and the accompanying poster, we highlight the regulation of rab gtpases by proteins that control their membrane association and activation state, and provide an overview of the cellular processes that are regulated by.
Toward a comprehensive map of the effectors of rab gtpases. The drosophila nephrocyte is a critical component of the fly renal system and bears structural and functional homology to podocytes and proximal tubule cells of the mammalian kidney. The rab family is a group of raslike small gtpases that regulate various types of intracellular membrane traffic in all eukaryotes. The golgi apparatus functions as the central station of membrane traffic in cells. The actual function of the lrrk2 protein is not yet clear, although it has been implicated in several pathways including synaptic vesicle regulation, endocytosis and membrane trafficking. Rab gtpases networks in membrane traffic in saccharomyces. Vesicle fusion is the merging of a vesicle with other vesicles or a part of a cell membrane. As key mediators of membrane trafficking, small gtpases from the rab family of proteins play critical roles in this process by acting as. The rab gtpases recruit peripheral membrane proteins to. Integrinmediated function of rab gtpases in cancer.
Ras analog in brain rab proteins are small guanosine triphosphatases gtpases that belong to the raslike gtpase superfamily, and they can regulate vesicle trafficking. Pdf the role of lrrk2 in the pathogenesis of parkinsons. In general, rab functions as a molecular switch by cycling between two nucleotide bound states, a gtpbound active state and a gdpbound inactive state, and active rab promotes various steps in membrane traffic, including vesicle budding from. The regulatory rab and arf gtpases for vesicular trafficking. The nutrient stressinduced small gtpase rab5 contributes. A series of rab gtpases, which control various steps in membrane traffic, act consecutively during the course of golgi maturation. Membraneanchored human rab gtpases directly mediate. Comprehensive functional analysis of rab gtpases in.
As mentioned above, rab gtpases transmit their signal by engaging effectors that often enact mechanical work propelling vesicle traffic. Intracellular trafficking network and autophagy of phbhhx. The emerging role of rab5 in membrane receptor trafficking. Slpra1a rab attenuate eix immune responses via degradation of leeix2 pattern recognition receptor l. Rab gtpases are one of the main coordinators of membrane domain formation and dynamics. In particular, the yeast counterparts of rab11, ypt31 and ypt32, are required for vesicle budding from the trans golgi network jedd et al. Rab gtpases are master regulators of eukaryotic endomembrane systems, particularly functioning in membrane tethering to confer the directionality of intracellular membrane trafficking. Right panel shows a merged image of tfnr staining shown as green, rab8a t22n. There are more than 60 members in humans and each of them is specifically localized to a subcellular membrane compartment, of which it controls the intracellular traffic.
Optogenetic oligomerization of rab gtpases regulates. It has been shown that rab proteins are involved in distinct membrane trafficking steps in endosomal and biosynthetic pathways by participating in the regulation of. The functions of yptrabs are themselves controlled by upstream regulators that. Rab gtpases act in a cascade in which rab11a activation of rab8a is independent of. Intracellular trafficking network of protein nanocapsules. The g2019s mutation within the lrrk2 gene, is the most common genetic cause of parkinsons, being responsible for 2040% of all familial pd cases, depending on the population under study. Rab27 effectors, pleiotropic regulators in secretory. Membrane traffic in the secretory pathway springerlink.
Through these activities, rab gtpases control compartment maturation. Dysregulation of vesicle trafficking leads to diverse pathological outcomes. Rab proteins are evolutionarily conserved with 5575% identity across species. Many distinct steps during trafficking including cargo sorting, vesicle transport, targeting, tethering, vesicle formation and vesicle fusion are regulated by specific members of the rab family of small gtpases 1, 2, 3.
Here we show that rab6, a golgiassociated rab, forms a complex with myosin ii. Rab gtpases and their interacting protein partners. Rab proteins are part of the large ras superfamily of small gtpases. He carried out a postdoctorate in marino zerials group at the european molecular biology laboratory, heidelberg, germany, from 1991 to 1994. Cib1 heterodimerization system results in lightmediated crosslinking and aggregation of different rab gtpases, disrupting membrane and endosomal. Distinct yet overlapping roles of rab gtpases on synaptic. To analyze this, we screened all caenorhabditis elegans rab gtpases and tre2bub2cdc16 tbc domain containing gtpaseactivating proteins gaps. Rab gtpases are important in delivering cargos to correct destinations and control vesicle budding, as well as the uncoating and motility of vesicles.
Here, we thoroughly tested seven purified rab gtpases in human, which localize at the various. Cellular functions of rab gtpases at a glance journal of. Rab proteins are small gtpases that act as essential regulators of vesicular trafficking. Neurons require highly specialized intracellular membrane trafficking, especially at synapses. In a second step, we merged the resulting clusters across genomes if at least. Rab proteins cycle between an inactive cytosolic gdpbound form and an active membraneassociated gtpbound form. Cytoplasmic control of rab family small gtpases through bag6. Rab small gtpases are the key regulators of diverse membrane trafficking events, including cargo sorting, vesicle budding, vesicle formation, vesicle transport along the cytoskeleton and docking, tethering and fusion of vesicles with target membranes in all eukaryotic cells 5, 6. Rab gtpases are involved in vesicle transport and trafficking. Rab gtpases function as molecular switches that alternate between two conformational states. Collaboration between two distinct rab small gtpase. Most functions of rab gtpases and their effectors are related to vesicular traffic between a donor and an acceptor compartment, and it is interesting to note that distinct rab effectors are involved in the sorting of cargo into budding vesicles, vesicle uncoating or vesicle motility along actin filaments or microtubules, as well as vesicle tethering to acceptor membranes stenmark, 2009. Members of the rab family of small gtpases are major regulators of macromolecular traffic in the secretory and endocytic pathways 1 4.
Ypt rab guanosine triphosphatases gtpases have emerged in the last decade as key regulators of protein transport in all eukaryotic cells. Rab27 is present on a wide range of lysosomerelated and other secretory organelles, and is involved in the intracellular transport of melanosomes in melanocytes, as well as in the regulation of secretion from endocrine and exocrine cells, cytotoxic tlymphocytes and platelets. Rab11arab8a cascade regulates the formation of tunneling. The denn differentially expressed in normal and neoplastic cells domain is an evolutionarily ancient protein module that is found in species as diverse as schizosaccharymyces pombe, arabidopsis thaliana, caenorhabditis elegans, drosophila melanogaster and humans. N2 membrane trafficking between organelles by vesiculotubular carriers is fundamental to the existence of eukaryotic cells.748 187 1220 1347 1498 396 1012 78 200 706 130 860 789 698 1217 1614 1131 411 341 1464 1144 901 1563 680 1313 396 1514 774 1390 1507 365 792 81 915 437 339 1427 776 468 1428 1411