Rab gtpase regulation of membrane identity europe pmc. Rab gtpases control intracellular vesicle traffic by acting as regulatable switches that recruit effector molecules when in their gtpbound form. Avni aschool of plant sciences and food security, tel aviv university, tel aviv, israel. So far, the structure of tbc1d15 or the tbc1d15rab complex has not been determined, thus, its catalytic mechanism on rab gtpases is still unclear. The rab family of small gtpases, comprising approximately 70 members, is the master regulators of intracellular vesicle transport. In addition to caveolae, several small rab gtpases have been implicated in ld function.
The nutrient stressinduced small gtpase rab5 contributes. Rab proteins are small monomeric gtpases forming the largest subgroup of the ras superfamily. Misereylenkei s, chalancon g, bardin s, formstecher e, goud b, et al. Slpra1a rab attenuate eix immune responses via degradation of leeix2 pattern recognition receptor l. He carried out a postdoctorate in marino zerials group at the european molecular biology laboratory, heidelberg, germany, from 1991 to 1994. Rab gtpases as coordinators of vesicle traffic nature. Here, we present the first systematic characterization of neuronal expression, subcellular localization, and function of rab gtpases in an organism with a brain. This paper describes affinity chromatography using all drosophila rabs with a mammalian ortholog. Oc differentiation, survival, and activity are regulated by numerous small gtpases, including those of the rab family, which are involved in plasma membrane delivery and lysosomal and autophagic degradation pathways.
This is a pdf file of an unedited manuscript that has been accepted for publication. Frontiers the puzzle of chloroplast vesicle transport. Rab gtpases are important in delivering cargos to correct destinations and control vesicle budding, as well as the uncoating and motility of vesicles. Aug 01, 2009 rab gtpases control intracellular vesicle traffic by acting as regulatable switches that recruit effector molecules when in their gtpbound form. Article addendum slpra1arab attenuate eix immune responses via degradation of leeix2 pattern recognition receptor l. Rabs are small gtpases 2025 kda that belong to the rab protein family, which is composed of more than 70 mammalian members and forms the largest branch of the ras superfamily. Integrinmediated function of rab gtpases in cancer progression. As key mediators of membrane trafficking, small gtpases from the rab family of proteins play critical roles in this process by acting as. Here, we present the first systematic characterization of neuronal expression, subcellular localization, and function of rab gtpases. Three systems transfer lipids, proteins and other important molecules through aqueous spaces to membraneenclosed compartments, via vesicles that bud from donor. Rab proteins cycle between an inactive cytosolic gdpbound form and an active membraneassociated gtpbound form. Significant plasticity in endosomal membrane transport pathways is. In the cytosol of plant cells vesicle transport occurs via secretory pathways among the endoplasmic reticulum network, golgi bodies, secretory granules, endosome, and plasma membrane. The functional coupling between multiple rab gtpases ensures the spatiotemporally coordinated regulation of vesicle traffic.
Sep 18, 2001 ypt rab guanosine triphosphatases gtpases have emerged in the last decade as key regulators of protein transport in all eukaryotic cells. Rab family small gtpases regulate membrane trafficking by. Originally, they were named as ra s genes from ra t b rain 1 but they are ubiquitously expressed in mammalian cells. Slpra1arab attenuate eix immune responses via degradation of. Vesicle traffic systems vtss transport cargo among the intracellular compartments of eukaryotic cells. As key mediators of membrane trafficking, small gtpases from the rab family of proteins play critical roles in this process by acting as molecular switches. A cartoon model of uvragrubicon in autophagosome and endosome maturation. Rab1 interaction with a gm effector complex regulates. Rab gtpases regulate cargo sorting, vesicle budding, membrane. Tubulovesicular trafficking in the exocytic and endocytic pathways is regulated by members of the rab gtpase family, which now comprises over 50 proteins. The active form of the rab proteins, which contains gtp, can recruit specific. Gtpases, tethering factors, snares and specific lipids is responsible for vesicle formation, stability, specific targeting and fusion.
Rab gtpases implicated in inherited and acquired disorders. 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. All images within this have either been created by my selfcowriter, have. For this reason, rab gtpases can be viewed as the coordinators of. Rab proteins temporally and spatially control vesicular transport. Lossoffunction mutations in rab18 cause warburg micro. Rab family small gtpases are master regulators of distinct steps of intracellular vesicle trafficking in eukaryotic cells. Regulation of vesicular traffic through rab organizers.
The nutrient stressinduced small gtpase rab5 contributes to the. N2 membrane trafficking between organelles by vesiculotubular carriers is fundamental to the existence of eukaryotic cells. Membrane trafficking between organelles by vesiculotubular carriers is fundamental to the existence of eukaryotic 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. One member of the rassuperfamily, rab, is involved in the regulation of vesicle trafficking, which is critical to endocytosis, biosynthesis, secretion, cell differentiation and cell growth. Rab gtpases interconvert between an active state in which a gtp molecule is bound to the enzyme and an inactive state in which a gdp molecule is bound to it. Rab gtpases are considered master regulators of membrane trafficking in all cells, and only very few rabs have known neuronspecific functions. Report lossoffunction mutations in rab18 cause warburg micro syndrome danai bem,1 shinichiro yoshimura,2,12 ricardo nunesbastos,2 frances f. Gtp bound rab proteins recruit effectormolecules e. Secretory rab gtpase 3c modulates il6stat3 pathway to. Apr 11, 2009 the root hair is one of the fastest growing cells in the plant. Uvrag the general acts as a strong activator for both pi3kc3 and hops, but it is only active if. Rab gtpases as coordinators of vesicle traffic md anderson. Members of the rab family of small gtpases are major regulators of macromolecular traffic in the secretory and endocytic pathways 1 4.
Each rab protein is localized to the cytoplasmic surface of a distinct membrane bound organelle 23, 24, 25 and appears to control a specific membrane transport pathway. Rab proteins are part of the large ras superfamily of small gtpases. Rab gtpases are master regulators of eukaryotic endomembrane systems, particularly functioning in membrane tethering to confer the directionality of intracellular membrane trafficking. A formal methods approach to predicting new features of. Cellular functions of rab gtpases at a glance journal of. Rab proteins control membrane trafficking by cycling between active gtp. Novel functions for rab gtpases in multiple aspects of tumour.
Nov 21, 2012 rab gtpases are master regulators of intracellular trafficking and, in recent years, their role in the control of different aspects of tumour progression has emerged. Coordination of ampa receptor trafficking by rab gtpases. Pdf the role of lrrk2 in the pathogenesis of parkinsons. Rabs are inactive when bound to gdp and are activated by exchanging gdp for gtp. Neurons require highly specialized intracellular membrane trafficking, especially at synapses.
Toward a comprehensive map of the effectors of rab gtpases. Since the discovery of the first yeast, rasrelated gtpase ypt1 gene and the landmark paper reporting the discovery of the sec4 gene sequence that first suggested a key role for these raslike gtpases in the control of membrane traffic, we now know that there are about 66 human rab proteins and 11 yeast rab related ypt proteins 3,4 that are master regulators of the secretory and. Jun 20, 2010 the nonprocessive motor, myosin ii, is shown to be an effector of the golgiassociated rab6 gtpase. Rabs also bind membrane lipids and act as molecular switches to support the targeted transport, docking, and fusion of a donor vesicle to a receptor compartment 11. Integrinmediated function of rab gtpases in cancer. Pdf rab gtpases as coordinators of vesicle traffic. Rab proteins in vesicle tethering despite their discovery more than 15 years ago, the precise. Cellular functions of rab gtpases at a glance journal of cell. Rab gtpases, with the help of their effectors ensure. Rab gtpases function as molecular switches that alternate between two conformational states. By virtue of prenylation moieties anchored to their c. 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.
Intracellular membrane trafficking is mediated by vesicular carriers from donor to. However, several observations described above have now demonstrated that it is more likely that transport between these two compartments occurs by a maturation process, rather than vesicle transport. The role of rab in inter vesicular trafficking youtube. Presynaptic neurotransmitter release is dominated by the synaptic vesicle sv cycle and entails the biogenesis, fusion, recycling, reformation or turnover of synaptic vesiclesa process involving bulk movement of membrane and proteins. However, it remains largely unclear how the expression and functions of rab proteins are regulated in response to extracellular or intracellular stimuli. The gdp dissociation inhibitor gdi solubilizes prenylated rab gtpases from and shuttles them between membranes in the form of a soluble cytosolic complex. Novel functions for rab gtpases in multiple aspects of.
Jun 10, 2015 a complex coordination of the cytoskeleton, motor proteins, vesicular coat proteins as well as rab. Distinct yet overlapping roles of rab gtpases on synaptic. Systematic discovery of rab gtpases with synaptic functions. The active form of the rab proteins, which contains gtp, can recruit specific binding. They seem to be involved in all aspects of vesicle trafficking. Jul 15, 2009 rab gtpases control intracellular vesicle traffic by acting as regulatable switches that recruit effector molecules when in their gtpbound form. Nov 10, 2014 rab gtpases organize cellular compartments by recruiting specific effectors to organelle membranes. Human rab gtpases are a family of about 60 enzymes that regulate a variety of processes within cells stenmark, 2009. To allow this rapid growth, continuous delivery of membrane and cell wall material to the growing tip of the hair cell is required.
In resorbing ocs, polarized vesicular trafficking pathways also result in formation of. The rassuperfamily of small g proteins is a family of gtp hydrolases that is regulated by gtpgdp binding states. Furthermore, mostly through their roles in vesicular transport, rab gtpases also control specialized. An endosome is a membranebound compartment inside a eukaryotic cell. Frontiers host cell rab gtpases in hepatitis b virus. It is an organelle of the endocytic membrane transport pathway originating from the trans golgi network. However, for many rabs, few, if any, effectors have been identified. Hutagalung ah, novick pj 2011 role of rab gtpases in membrane traffic and cell physiology. Rab gtpases have been studied for several decades but. Molecules or ligands internalized from the plasma membrane can follow this pathway all the way to lysosomes for degradation, or they can be recycled back to the plasma membrane, in the endocytic cycle. Rab proteins are key mediators of vesicle transport. Membrane extraction of rab proteins by gdp dissociation. Another unique identifying feature that differs between the various classes of endosomes is the lipid composition in their membranes.
Osteoclasts ocs are boneresorbing cells that maintain bone homeostasis. Rab gtpases are involved in regulation of vesicle formation, its uncoating and transport, while tethering factors and snares facilitate the membrane fusion processes. A large group of small rab gtpases which mediate secretory and endosomal membrane transport, as well as autophagosome biogenesis, are essential components of. Request pdf rab gtpases and microtubule motors rab proteins are a family of. The rab gtpases recruit peripheral membrane proteins to intracellular organelles. Coats, tethers, rabs, and snares work together to mediate the intracellular destination of a transport vesicle. These rab effectors typically mediate the motility of organelles and vesicles and contribute to the specificity of membrane traffic. Rab proteins and the compartmentalization of the endosomal system. Cytoplasmic control of rab family small gtpases through bag6. Rab proteins are members of the ras superfamily of small molecular weight gtpases that function as molecular switches by cycling between inactive gdp. Several interesting questions about vtss translate to combinatorial search and.
Up to date almost 70 different rab proteins have been identified in humans, playing a central role in the regulation of intracellular. Cytoplasmic control of rab family small gtpases through. Stenmark h 2009 rab gtpases as coordinators of vesicle traffic. Yptrab guanosine triphosphatases gtpases have emerged in the last decade as key regulators of protein transport in all eukaryotic cells. 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. Rab gtpases regulate endocytosis by decorating intracellular vesicles and. Rab family proteins are important in regulating signal transduction and cellular processes such as differentiation, proliferation, vesicle transport, nuclear assembly, and cytoskeleton formation. Rabmediated vesicle trafficking in cancer hongtai tzeng1 and yiching wang1,2 abstract a large group of small rab gtpases which mediate secretory and endosomal membrane transport, as well as autophagosome biogenesis, are essential components of vesicle trafficking machinery.
Rab gtpases and microtubule motors request pdf researchgate. The complexity of vesicle transport factors in plants. The functions of yptrabs are themselves controlled by upstream regulators that stimulate both their nucleotide. Distinct yet overlapping roles of rab gtpases on synaptic vesicles. Rab gtpases bind specific effector proteins which control the targeting. 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. Gtp can then be cleaved by the endogenous gtpase activity of the rab to produce the gdpbound form. Here, we thoroughly tested seven purified rab gtpases in human, which localize at the various.
The ras rat sarcoma superfamily of small gtpases is broadly subdivided into five groups. Rab and actomyosindependent fission of transport vesicles at. Rab gtpases play an important role in specifying transport pathways in the. Rab gtpases emerge as universal regulators for multiple events ranging from vesicle formation, uncoating and transport to tethering process, and to the final vesicle fusion. Functional impairments of rab pathways are associated with diseases, such as immunodeficiencies, cancer and neurological disorders. Since the discovery of the first yeast, rasrelated gtpase ypt1 gene and the landmark paper reporting the discovery of the sec4 gene sequence that first suggested a key role for these raslike gtpases in the control of membrane traffic, we now know that there are about 66 human rab proteins and 11 yeast rabrelated ypt proteins 3,4 that are master regulators of the secretory. Rab5 proteins that ensure adaptable vesicle trafficking and vacuolar. Rab gtpases regulate membrane trafficking, cell growth and differentiation. The functions of yptrabs are themselves controlled by upstream regulators that. The actomyosin machinery is involved in the fission of transport carriers from golgi membranes. Additionally, vesicle transport has also been discussed between other compartments shown in grey circles not discussed in the manuscript. 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. Eukaryotic cells have evolved an extensive internal membrane apparatus that comprises the.
Nov 19, 2018 hepatitis b virus hbv is a leading cause of liver disease and is presently estimated to infect more than 250 million humans. The extremely successful spread of this virus among the human population is explained by its effective transmission strategies and its manifold particle types, including virions, empty envelopes and naked capsids. Feb 11, 2014 human rab gtpases are a family of about 60 enzymes that regulate a variety of processes within cells stenmark, 2009. However, some rab proteins have been reported to be. Pdf rab gtpases as coordinators of vesicle traffic scinapse.
Dysregulation of vesicle trafficking leads to diverse pathological outcomes, some of. Small regulatory rab gtpases belong to the group of conserved trafficking proteins that govern membrane traffic in all eukaryotes. The nonprocessive motor, myosin ii, is shown to be an effector of the golgiassociated rab6 gtpase. Crosstalk between multiple rab gtpases through shared effectors, or through effectors that recruit selective rab activators, ensures the spatiotemporal regulation of vesicle traffic. However, how exactly rab gtpases themselves act upon membrane tethering processes has remained enigmatic. A large group of small rab gtpases which mediate secretory and endosomal membrane transport, as well as autophagosome biogenesis, are essential components of vesicle trafficking machinery. A short video representation of the role rab gtpases play in controlling vesicular transport, using rab5a as an example. Altmetric rab gtpases as coordinators of vesicle traffic. Loss of rab gtpase activity is known to cause many inherited disorders. Nov 19, 2009 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. Rab gtpases, a large family of ras small gtpases, play crucial roles in normal human physiology by regulating membrane identity and vesicle trafficking, including budding, sorting, uncoating, motility, tethering, and fusion. Membrane trafficking is regulated by small raslike gdpgtp binding proteins of the rab subfamily rab gtpases that cycle between membranes and cytosol depending on their nucleotide state.
Rab gtpases control intracellular membrane traffic by recruiting specific effector proteins to restricted membranes in a gtpdependent manner. As hbv capsid assembly can be recapitulated in bacteria and cell free systems. A complex coordination of the cytoskeleton, motor proteins, vesicular coat proteins as well as rab. Rab proteins as molecular coordinators of membrane trafficking. Rabs are important regulators of vesicle trafficking, which is one of the mechanisms controlling cellular functions, including cell proliferation invasion, signal. Ijms free fulltext multitasking rab proteins in autophagy and. Small gtpases regulate various cellular pathways and can be divided into five subfamilies. However, some rab proteins have been reported to be necessary for the adhesion. Rab gtpases and their interacting protein partners. Each rab protein is localized to the cytoplasmic surface of a distinct membrane bound organelle, and appears to control a specific membrane transport pathway. Rab gtpases, with the help of their effectors ensure the spatiotemporal regulation of vesicle traffic.
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