Indeed, even though actin polymerization by itself can promote membrane bending for endocytosis as shown for example in yeast 100, 101, molecular motors together with the cytoskeleton also influence. Rab gtpases and their interacting protein partners. Rab gtpases control intracellular vesicle traffic by acting as regulatable switches that recruit effector molecules when in their gtpbound form. By virtue of prenylation moieties anchored to their c. Rab gtpases were first linked to vesicle transport by groundbreaking genetic screens for mutants defective in protein secretion novick et al.
The rab family of small gtpases, comprising approximately 70 members, is the master regulators of intracellular vesicle transport. Detailed references are given in the additional file b. Rab gtpases are involved in vesicle transport and trafficking. Neurons require highly specialized intracellular membrane trafficking, especially at synapses. Distinct yet overlapping roles of rab gtpases on synaptic. Vesicle trafficking between compartments is essential for cellular function and intercellular communication. Small gtpases rab8a and rab11a are dispensable for rhodopsin transport in mouse photoreceptors. Approximately 70 types of rabs have now been identified in humans. 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. Dysregulation of vesicle trafficking leads to diverse pathological outcomes, some of which are.
The rab family of proteins is a member of the ras superfamily of small g proteins. N2 membrane trafficking between organelles by vesiculotubular carriers is fundamental to the existence of eukaryotic cells. The nutrient stressinduced small gtpase rab5 contributes. Cellular functions of rab gtpases at a glance journal of. Rab proteins are key mediators of vesicle transport. Slpra1a rab attenuate eix immune responses via degradation of leeix2 pattern recognition receptor l. Optogenetic oligomerization of rab gtpases regulates.
This is a pdf file of an unedited manuscript that has. Integrinmediated function of rab gtpases in cancer progression. Furthermore, mostly through their roles in vesicular transport, rab gtpases also control specialized. Validated effectors include traffic proteins and those of unknown function. Ras analog in brain rab proteins are small guanosine triphosphatases gtpases that belong to the raslike gtpase superfamily, and they can regulate vesicle trafficking. Reconstitution of membrane tethering mediated by rabfamily small. 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. Crosstalk between multiple rab gtpases through shared effectors, or through effectors that recruit selective rab activators, ensures the spatiotemporal regulation of vesicle traffic. Switching of rabs from gdp to gtpbound states provides on. Functional impairments of rab pathways are associated with diseases, such as immunodeficiencies, cancer and neurological disorders. Novel functions for rab gtpases in multiple aspects of. Rab gtpases regulate many steps of membrane trafficking, including vesicle formation, vesicle movement along actin. Stenmarkrab gtpases as coordinators of vesicle traffic.
Rab gtpases are considered master regulators of membrane trafficking in all cells, and only very few rabs have known neuronspecific functions. Intracellular membrane trafficking is mediated by vesicular carriers from donor to acceptor. Rab gtpases regulate endocytosis by decorating intracellular vesicles and targeting these vesicles. Integrinmediated function of rab gtpases in cancer. Nevertheless, indeed whether and how rab gtpases and their. The structure of glycans that decorate proteins and lipids is largely dictated by biosynthetic reactions occurring in the golgi apparatus.
Bridging the gap between glycosylation and vesicle traffic. Early endosome marker rab5 gtpase, a key member of the rab family, plays a crucial role in endocytosis and membrane transport. Secretory rab gtpase 3c modulates il6stat3 pathway to. Rab and arf gtpases interact with motor proteins not only to mediate vesicle and organelle motility, but also to control membrane remodeling. Each rab protein is localized to the cytoplasmic surface of a distinct membrane bound organelle 23, 24, 25 and appears to control a.
Rab gtpases play an important role in specifying transport pathways in the intracellular membrane. Other participants in this process are the rab family of gtpases, which regulate traffic between different cellular compartments and which are implicated in directing vesicles to their appropriate target compartments. In its simplest form, this model predicts that rab proteins act as molecular tags to specify the right acceptor compartment for a given transport vesicle. Rab gtpases as coordinators of vesicle traffic nature. Pdf small gtpases rab8a and rab11a are dispensable for. Rab gtpases, with the help of their effectors ensure the spatiotemporal regulation of vesicle traffic. Pdf integrinmediated function of rab gtpases in cancer. Soon after their discovery three decades ago, it was appreciated that rab gtpases localise to specific membrane domains and organelle membranes within eukaryotic cells.
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 were first considered proteins that ensured that a transport vesicle leaving one intracellular compartment is deposited in the appropriate acceptor compartment. Sec4, rab8 in humans, was found to function in the terminal step of the secretory pathway, delivery of golgiderived transport vesicles to the cell surface salminen and novick, 1987. Rab gtpases are important in delivering cargos to correct destinations and control vesicle budding, as well as the uncoating and motility of vesicles. The emerging role of rab5 in membrane receptor trafficking. This biosynthesis relies on the relative distribution of glycosyltransferases and glycosidases, which is maintained by retrograde vesicle traffic between golgi cisternae. The latter mechanism ensures the correct assembly of some multisubunit membrane proteins. Rab proteins generally possess a gtpase fold, which consists of a sixstranded beta sheet which is flanked by five alpha helixes. The snare proteins are just one component of the vesicle targeting system. 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 proteins are evolutionarily conserved with 5575 % identity across species. We focus on the rab enzymes, critical organisers of the trafficking. Toward a comprehensive map of the effectors of rab gtpases. The first rab gtpases identified through yeast genetics, sec4 rab8 and ypt1 rab1, were shown to have crucial roles in vesicle transport in the exocytic pathway hutagalung and novick, 2011, but studies in multiple organisms have identified a number of rab gtpases that also control endocytic membrane traffic wandingerness and zerial, 2014.
Membrane trafficking between organelles by vesiculotubular carriers is fundamental to the existence of eukaryotic cells. Specific rab protein together with the cognate effectors coordinates the dynamics of trafficking pathway and determines the cargo proteins destination. An interesting model explains this by a linear arrangement of rab gtpases. 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. Small regulatory rab gtpases belong to the group of conserved trafficking proteins that govern membrane traffic in all eukaryotes. Glycosylation is recognized as a vitally important posttranslational modification. Pdf the role of lrrk2 in the pathogenesis of parkinsons. Rab30 is required for the morphological integrity of the. The class v myosins have been implicated in the transport of diverse cargoes such as melanosomes in pigment cells, synaptic vesicles in neurons, rna transcripts in a variety of cell types, and organelles such as the endoplasmic reticulum. Molecular understanding of viral maturation and egress. Comprehensive knockout analysis of the rab family gtpases in. Rab proteins temporally and spatially control vesicular transport. An external file that holds a picture, illustration, etc. Thousands of rab gtpases for the cell biologist plos.
Our resident insectivore, mole, has started a new series the corona files. 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 regulate membrane trafficking, cell growth and differentiation. Genomewide analysis shows association of epigenetic. Here, we present the first systematic characterization of neuronal expression, subcellular localization, and function of rab gtpases in an organism with a brain. 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. Rab gtpases and tethering in the yeast endocytic pathway. Rab11 regulates exocytosis of recycling vesicles at the. However, manual identification of rab repertoires is tedious and. Rab gtpases implicated in inherited and acquired disorders. Analysis of the interactions between rab gtpases and class. Membrane trafficking between organelles by vesiculotubular carriers isfundamental to the existence of eukaryotic cells. Rab gtpases control intracellular membrane traffic by recruiting specific effector proteins to restricted membranes in a gtpdependent manner.
Rab regulation by gefs and gaps during membrane traffic. Rab gtpases as coordinators of vesicle traffic semantic scholar. Rab proteins, the largest subfamily of the ras superfamily of small gproteins, are central. Rab and actomyosindependent fission of transport vesicles. Rab proteins alternate between an activated gtpbound state and an inactivated gdpbound state. Pdf rab gtpases as coordinators of vesicle traffic. Rabmediated vesicle trafficking in cancer journal of. The traffic using copi vesicles is also important for er quality control. Stenmark h 2009 rab gtpases as coordinators of vesicle traffic. The functional coupling between multiple rab gtpases ensures the spatiotemporally coordinated regulation of vesicle traffic.
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