scholarly journals Large-Scale Profiling of Rab GTPase Trafficking Networks: The Membrome

2005 ◽  
Vol 16 (8) ◽  
pp. 3847-3864 ◽  
Author(s):  
Cemal Gurkan ◽  
Hilmar Lapp ◽  
Christelle Alory ◽  
Andrew I. Su ◽  
John B. Hogenesch ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Large Scale ◽  
Building Blocks ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Coding System ◽  
Clustering Methods ◽  
Protein Activity ◽  
Organ Systems ◽  
Hierarchical Clustering Methods

Rab GTPases and SNARE fusion proteins direct cargo trafficking through the exocytic and endocytic pathways of eukaryotic cells. We have used steady state mRNA expression profiling and computational hierarchical clustering methods to generate a global overview of the distribution of Rabs, SNAREs, and coat machinery components, as well as their respective adaptors, effectors, and regulators in 79 human and 61 mouse nonredundant tissues. We now show that this systems biology approach can be used to define building blocks for membrane trafficking based on Rab-centric protein activity hubs. These Rab-regulated hubs provide a framework for an integrated coding system, the membrome network, which regulates the dynamics of the specialized membrane architecture of differentiated cells. The distribution of Rab-regulated hubs illustrates a number of facets that guides the overall organization of subcellular compartments of cells and tissues through the activity of dynamic protein interaction networks. An interactive website for exploring datasets comprising components of the Rab-regulated hubs that define the membrome of different cell and organ systems in both human and mouse is available at http://www.membrome.org/ .

scholarly journals The Hsp90 Chaperone Complex Regulates GDI-dependent Rab Recycling

2006 ◽  
Vol 17 (8) ◽  
pp. 3494-3507 ◽  
Author(s):  
Christine Y. Chen ◽  
William E. Balch
Keyword(s):  
Rab Gtpase ◽  
Rab Gtpases ◽  
Coding System ◽  
Golgi Transport ◽  
Guanine Nucleotide Dissociation Inhibitor ◽  
Hsp90 Activity ◽  
Hsp90 Chaperone ◽  
Chaperone Complex ◽  
Hsp 90 ◽  
Synaptic Vesicle Fusion

Rab GTPase regulated hubs provide a framework for an integrated coding system, the membrome network, that controls the dynamics of the specialized exocytic and endocytic membrane architectures found in eukaryotic cells. Herein, we report that Rab recycling in the early exocytic pathways involves the heat-shock protein (Hsp)90 chaperone system. We find that Hsp90 forms a complex with guanine nucleotide dissociation inhibitor (GDI) to direct recycling of the client substrate Rab1 required for endoplasmic reticulum (ER)-to-Golgi transport. ER-to-Golgi traffic is inhibited by the Hsp90-specific inhibitors geldanamycin (GA), 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), and radicicol. Hsp90 activity is required to form a functional GDI complex to retrieve Rab1 from the membrane. Moreover, we find that Hsp90 is essential for Rab1-dependent Golgi assembly. The observation that the highly divergent Rab GTPases Rab1 involved in ER-to-Golgi transport and Rab3A involved in synaptic vesicle fusion require Hsp90 for retrieval from membranes lead us to now propose that the Hsp90 chaperone system may function as a general regulator for Rab GTPase recycling in exocytic and endocytic trafficking pathways involved in cell signaling and proliferation.

LRRK2 and Rab GTPases

2018 ◽  
Vol 46 (6) ◽  
pp. 1707-1712 ◽  
Author(s):  
Suzanne R. Pfeffer
Keyword(s):  
Membrane Trafficking ◽  
Protein Function ◽  
Short Review ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Rab Protein ◽  
Complex Interactions ◽  
Preferential Binding ◽  
Bona Fide ◽  
Mutant Lrrk2

Leucine-rich repeat kinase 2 (LRRK2) is mutated in familial Parkinson's disease, and pathogenic mutations activate the kinase activity. A tour de force screen by Mann and Alessi and co-workers identified a subset of Rab GTPases as bona fide LRRK2 substrates. Rab GTPases are master regulators of membrane trafficking and this short review will summarize what we know about the connection between LRRK2 and this family of regulatory proteins. While, in most cases, Rab GTPase phosphorylation is predicted to interfere with Rab protein function, the discovery of proteins that show preferential binding to phosphorylated Rabs suggests that more complex interactions may also contribute to mutant LRRK2-mediated pathology.

scholarly journals Rab GTPases: Emerging Oncogenes and Tumor Suppressive Regulators for the Editing of Survival Pathways in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 259 ◽  
Author(s):  
Priya D. Gopal Krishnan ◽  
Emily Golden ◽  
Eleanor A. Woodward ◽  
Nathan J. Pavlos ◽  
Pilar Blancafort
Keyword(s):  
Membrane Trafficking ◽  
Molecular Mechanisms ◽  
Intracellular Localization ◽  
Cellular Migration ◽  
Rab Gtpase ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Aberrant Expression ◽  
Post Translational Modifications ◽  
Survival Pathways

The Rab GTPase family of proteins are mediators of membrane trafficking, conferring identity to the cell membranes. Recently, Rab and Rab-associated factors have been recognized as major regulators of the intracellular positioning and activity of signaling pathways regulating cell growth, survival and programmed cell death or apoptosis. Membrane trafficking mediated by Rab proteins is controlled by intracellular localization of Rab proteins, Rab-membrane interactions and GTP-activation processes. Aberrant expression of Rab proteins has been reported in multiple cancers such as lung, brain and breast malignancies. Mutations in Rab-coding genes and/or post-translational modifications in their protein products disrupt the cellular vesicle trafficking network modulating tumorigenic potential, cellular migration and metastatic behavior. Conversely, Rabs also act as tumor suppressive factors inducing apoptosis and inhibiting angiogenesis. Deconstructing the signaling mechanisms modulated by Rab proteins during apoptosis could unveil underlying molecular mechanisms that may be exploited therapeutically to selectively target malignant cells.

scholarly journals Cell cycle–dependent phosphorylation of Sec4p controls membrane deposition during cytokinesis

2016 ◽  
Vol 214 (6) ◽  
pp. 691-703 ◽  
Author(s):  
Dante Lepore ◽  
Olya Spassibojko ◽  
Gabrielle Pinto ◽  
Ruth N. Collins
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Membrane Trafficking ◽  
Intracellular Trafficking ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Positive Regulator ◽  
Physiological Relevance ◽  
A Cell ◽  
Cycle Dependent

Intracellular trafficking is an essential and conserved eukaryotic process. Rab GTPases are a family of proteins that regulate and provide specificity for discrete membrane trafficking steps by harnessing a nucleotide-bound cycle. Global proteomic screens have revealed many Rab GTPases as phosphoproteins, but the effects of this modification are not well understood. Using the Saccharomyces cerevisiae Rab GTPase Sec4p as a model, we have found that phosphorylation negatively regulates Sec4p function by disrupting the interaction with the exocyst complex via Sec15p. We demonstrate that phosphorylation of Sec4p is a cell cycle–dependent process associated with cytokinesis. Through a genomic kinase screen, we have also identified the polo-like kinase Cdc5p as a positive regulator of Sec4p phosphorylation. Sec4p spatially and temporally localizes with Cdc5p exclusively when Sec4p phosphorylation levels peak during the cell cycle, indicating Sec4p is a direct Cdc5p substrate. Our data suggest the physiological relevance of Sec4p phosphorylation is to facilitate the coordination of membrane-trafficking events during cytokinesis.

scholarly journals Chlamydia pneumoniae Inclusion Membrane Protein Cpn0585 Interacts with Multiple Rab GTPases

2007 ◽  
Vol 75 (12) ◽  
pp. 5586-5596 ◽  
Author(s):  
Claudio Cortes ◽  
Kimberly A. Rzomp ◽  
Amy Tvinnereim ◽  
Marci A. Scidmore ◽  
Benjamin Wizel
Keyword(s):  
Membrane Protein ◽  
Host Cell ◽  
Membrane Trafficking ◽  
Chlamydia Pneumoniae ◽  
Fluorescent Protein ◽  
Ectopic Expression ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Inclusion Membrane ◽  
Green Fluorescent

ABSTRACT Chlamydiae are intracellular bacteria that develop within a membrane-bound vacuole called an inclusion. To ensure that the inclusion is a safe niche for chlamydial replication, chlamydiae exploit a number of host cell processes, including membrane-trafficking pathways. Recently, several Rab GTPases were found to associate with the inclusions of various chlamydial species. Here we report that Cpn0585, a Chlamydia pneumoniae inclusion membrane protein (Inc), interacts with multiple Rab GTPases. The results from yeast two-hybrid experiments revealed that an amino-terminally truncated form of Cpn0585 (Cpn0585102-651) interacts with Rab1, Rab10, and Rab11 but not with Rab4 or Rab6. Cpn0585-Rab GTPase interactions are direct and GTP dependent as shown in glutathione S-transferase pull-down assays using native and recombinant Cpn0585. In C. pneumoniae-infected HEp-2 cells transfected with enhanced green fluorescent protein (EGFP)-tagged Rab GTPases, the colocalization with Cpn0585 at the inclusion membrane was partial for EGFP-Rab1 and EGFP-Rab10, but extensive for wild-type EGFP-Rab11A and the constitutively active GTPase-deficient EGFP-Rab11AQ70L. Moreover, Cpn0585 colocalized with EGFP-Rab11AQ70L as early as 2 h postinfection. Upon delivery into live C. pneumoniae-infected cells, Cpn0585628-651-specific antibodies bound to the inclusion membrane, demonstrating that the Rab GTPase-interacting domain of Cpn0585 faces the host cell cytosol. Finally, ectopic expression of Cpn0585102-651 partially inhibited the development of C. pneumoniae inclusions in EGFP. but not in EGFP-Rab11AQ70L-expressing HEp-2 cells. Collectively, these data suggest that Cpn0585 is involved in the recruitment of Rab GTPases to the inclusion membrane and that interfering with this function may adversely impact the fitness of the C. pneumoniae inclusion for chlamydial replication.

scholarly journals Rab GTPases: master regulators that establish the secretory and endocytic pathways

2017 ◽  
Vol 28 (6) ◽  
pp. 712-715 ◽  
Author(s):  
Suzanne R. Pfeffer
Keyword(s):  
Membrane Trafficking ◽  
Membrane Microdomains ◽  
Rab Gtpase ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Open Questions ◽  
Endocytic Pathways

Several of the most important discoveries in the field of membrane traffic have come from studies of Rab GTPases by Marino Zerial and Peter Novick and their colleagues. Zerial was the first to discover that Rab GTPases represent identity markers for different membrane-bound compartments, and each Rab organizes a collection of specific effectors into function-specifying membrane microdomains to carry out receptor trafficking. Novick discovered that the order (and thus polarity) of Rab GTPases along the secretory and endocytic pathways are established by their specific, cognate guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which partner with one Rab to regulate the subsequent- and prior-acting Rabs. Such so-called Rab cascades have evolved to establish domains that contain unique Rab proteins and their cognate effectors, which drive all steps of membrane trafficking. These findings deserve much broader recognition by the biomedical research community and are highlighted here, along with open questions that require serious attention for full understanding of the molecular basis of Rab GTPase-regulated membrane trafficking in eukaryotic cells.

scholarly journals Multiplex image-based autophagy RNAi screening identifies SMCR8 as ULK1 kinase activity and gene expression regulator

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jennifer Jung ◽  
Arnab Nayak ◽  
Véronique Schaeffer ◽  
Tatjana Starzetz ◽  
Achim K Kirsch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Membrane Trafficking ◽  
Gene Locus ◽  
Kinase Activity ◽  
Degradation Pathway ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Mrna Expression Analysis ◽  
Different Populations

Autophagy is an intracellular recycling and degradation pathway that depends on membrane trafficking. Rab GTPases are central for autophagy but their regulation especially through the activity of Rab GEFs remains largely elusive. We employed a RNAi screen simultaneously monitoring different populations of autophagosomes and identified 34 out of 186 Rab GTPase, GAP and GEF family members as potential autophagy regulators, amongst them SMCR8. SMCR8 uses overlapping binding regions to associate with C9ORF72 or with a C9ORF72-ULK1 kinase complex holo-assembly, which function in maturation and formation of autophagosomes, respectively. While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. The latter phenotype involved association of SMCR8 with the ULK1 gene locus. Global mRNA expression analysis revealed that SMCR8 regulates transcription of several other autophagy genes including WIPI2. Collectively, we established SMCR8 as multifaceted negative autophagy regulator.

scholarly journals Regulation of ER-phagy by a Ypt/Rab GTPase module

2013 ◽  
Vol 24 (19) ◽  
pp. 3133-3144 ◽  
Author(s):  
Zhanna Lipatova ◽  
Ankur H. Shah ◽  
Jane J. Kim ◽  
Jonathan W. Mulholland ◽  
Nava Segev
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Trafficking ◽  
Eukaryotic Cells ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Cellular Compartment ◽  
Selective Autophagy ◽  
Downstream Effector ◽  
Golgi Transport ◽  
Autophagy Pathway

Accumulation of misfolded proteins on intracellular membranes has been implicated in neurodegenerative diseases. One cellular pathway that clears such aggregates is endoplasmic reticulum autophagy (ER-phagy), a selective autophagy pathway that delivers excess ER to the lysosome for degradation. Not much is known about the regulation of ER-phagy. The conserved Ypt/Rab GTPases regulate all membrane trafficking events in eukaryotic cells. We recently showed that a Ypt module, consisting of Ypt1 and autophagy-specific upstream activator and downstream effector, regulates the onset of selective autophagy in yeast. Here we show that this module acts at the ER. Autophagy-specific mutations in its components cause accumulation of excess membrane proteins on aberrant ER structures and induction of ER stress. This accumulation is due to a block in transport of these membranes to the lysosome, where they are normally cleared. These findings establish a role for an autophagy-specific Ypt1 module in the regulation of ER-phagy. Moreover, because Ypt1 is a known key regulator of ER-to-Golgi transport, these findings establish a second role for Ypt1 at the ER. We therefore propose that individual Ypt/Rabs, in the context of distinct modules, can coordinate alternative trafficking steps from one cellular compartment to different destinations.

scholarly journals Structural Clues to Rab GTPase Functional Diversity

2005 ◽  
Vol 280 (16) ◽  
pp. 15485-15488 ◽  
Author(s):  
Suzanne R. Pfeffer
Keyword(s):  
Structural Analysis ◽  
Functional Diversity ◽  
Membrane Trafficking ◽  
Crystallographic Analysis ◽  
Protein Family ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Important Protein ◽  
Partner Proteins ◽  
Insight Into

Rab GTPases are key regulators of membrane trafficking in eukaryotes. Recent structural analysis of a number of Rabs, either alone or in complex with partner proteins, has provided new insight into the importance of both conserved and non-conserved features of these proteins that specify their unique functions and localizations. This review will highlight what we have learned from crystallographic analysis of this important protein family.

scholarly journals Arf1 orchestrates Rab GTPase conversion at the trans-Golgi network

2021 ◽  
pp. mbc.E20-10-0664
Author(s):  
Laura L. Thomas ◽  
Carolyn M. Highland ◽  
J. Christopher Fromme
Keyword(s):  
Membrane Trafficking ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Membrane Domains ◽  
Trans Golgi Network ◽  
Important Regulator ◽  
And Function ◽  
Golgi Network ◽  
New Evidence

Rab family GTPases are key organizers of membrane trafficking and function as markers of organelle identity. Accordingly, Rab GTPases often occupy specific membrane domains and mechanisms exist to prevent the inappropriate mixing of distinct Rab domains. The yeast Golgi complex can be divided into two broad Rab domains: Ypt1 (Rab1) and Ypt6 (Rab6) are present at the early/medial Golgi and sharply transition to Ypt31/32 (Rab11) at the late Golgi/ trans-Golgi network (TGN). This Rab conversion has been attributed to GAP cascades in which Ypt31/32 recruits the Rab-GAPs Gyp1 and Gyp6 to inactivate Ypt1 and Ypt6, respectively. Here we report that Rab transition at the TGN involves additional layers of regulation. We provide new evidence confirming the TRAPPII complex as an important regulator of Ypt6 inactivation and uncover an unexpected role of the Arf1 GTPase in recruiting Gyp1 to drive Ypt1 inactivation at the TGN. Given its established role in directly recruiting TRAPPII to the TGN, Arf1 is therefore a master regulator of Rab conversion on maturing Golgi compartments.

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