New links between vesicle coats and Rab-mediated vesicle targeting

Angers, Cortney G.; Merz, Alexey J.

doi:10.1016/j.semcdb.2010.07.003

Cited by 68 publications

(77 citation statements)

References 144 publications

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“…Association of cytosolic proteins to their side of endosomal membranes is instrumental in their further fate. The Rab family, especially Rab5, is a key regulatory component for this process and, together with other coating proteins, decisive for selection of the targeted cell compartment [95]. Motor proteins are responsible for directed movement along actin-and tubulin filaments to reach the target organelles [96].…”

Section: Cellular Uptake and Intracellular Traffickingmentioning

confidence: 99%

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

Lorenzer

Dirin

Winkler

et al. 2015

Journal of Controlled Release

246

204

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Therapeutic gene silencing promises significant progress in pharmacotherapy, including considerable expansion of the druggable target space and the possibility for treating orphan diseases. Technological hurdles have complicated the efficient use of therapeutic oligonucleotides, and siRNA agents suffer particularly from insufficient pharmacokinetic properties and poor cellular uptake. Intense development and evolution of delivery systems have resulted in efficient uptake predominantly in liver tissue, in which practically all nanoparticulate and liposomal delivery systems show the highest accumulation. The most efficacious strategies include liposomes and bioconjugations with N-acetylgalactosamine. Both are in early clinical evaluation stages for treatment of liver-associated diseases. Approaches for achieving knockdown in other tissues and tumors have been proven to be more complicated. Selective targeting to tumors may be enabled through careful modulation of physical properties, such as particle size, or by taking advantage of specific targeting ligands. Significant barriers stand between sufficient accumulation in other organs, including endothelial barriers, cellular membranes, and the endosome. The brain, which is shielded by the blood-brain barrier, is of particular interest to facilitate efficient oligonucleotide therapy of neurological diseases. Transcytosis of the blood-brain barrier through receptor-specific docking is investigated to increase accumulation in the central nervous system. In this review, the current clinical status of siRNA therapeutics is summarized, as well as innovative and promising preclinical concepts employing tissue- and tumor-targeted ligands. The requirements and the respective advantages and drawbacks of bioconjugates and ligand-decorated lipid or polymeric particles are discussed.

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Section: Cellular Uptake and Intracellular Traffickingmentioning

confidence: 99%

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

Lorenzer

Dirin

Winkler

et al. 2015

Journal of Controlled Release

246

204

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“…Among the more than 60 Rabs encoded in mammalian genomes, several are known to regulate protein coats (37) or microtubule motors (38). However, the role of Rab proteins in somatodendritic-axonal polarity has not been assessed directly.…”

Section: Significancementioning

confidence: 99%

Rab5 and its effector FHF contribute to neuronal polarity through dynein-dependent retrieval of somatodendritic proteins from the axon

Guo

Farı́as

Mattera

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

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An open question in cell biology is how the general intracellular transport machinery is adapted to perform specialized functions in polarized cells such as neurons. Here we illustrate this adaptation by elucidating a role for the ubiquitous small GTPase Ras-related protein in brain 5 (Rab5) in neuronal polarity. We show that inactivation or depletion of Rab5 in rat hippocampal neurons abrogates the somatodendritic polarity of the transferrin receptor and several glutamate receptor types, resulting in their appearance in the axon. This loss of polarity is not caused primarily by increased transport from the soma to the axon but rather by decreased retrieval from the axon to the soma. Retrieval is also dependent on the Rab5 effector Fused Toes (FTS)-Hook-FTS and Hook-interacting protein (FHIP) (FHF) complex, which interacts with the minus-enddirected microtubule motor dynein and its activator dynactin to drive a population of axonal retrograde carriers containing somatodendritic proteins toward the soma. These findings emphasize the importance of both biosynthetic sorting and axonal retrieval for the polarized distribution of somatodendritic receptors at steady state.Rab5 | FHF complex | dynein | neuronal polarity | retrograde transport N eurons are highly polarized cells with distinct somatodendritic and axonal domains. Synaptic inputs are received through the somatodendritic domain, integrated at the axon initial segment (AIS), and propagated along the axon for transmission to downstream cells. To accomplish these specialized functions, each neuronal domain is endowed with a distinct set of proteins. A fundamental but still largely unanswered question is how neurons establish and maintain this polarized distribution of proteins throughout their lifetimes. The available evidence indicates that the mechanisms of polarized sorting in neurons are quite complex (1-3). Newly synthesized transmembrane proteins travel together from their site of synthesis in the rough endoplasmic reticulum (ER) to the Golgi complex. Once they reach the trans-Golgi network (TGN), the proteins are sorted into different membraneenclosed transport carriers destined for the somatodendritic or axonal domains (4-8). However, the efficiency of this biosynthetic sorting varies for different proteins and is often incomplete. Other processes, such as compartment-specific retention, retrieval, or transcytosis, additionally contribute to establishing the overall distribution of proteins between the somatodendritic and axonal domains and to their localization to specialized subdomains (5, 9-17).The selective incorporation of transmembrane proteins into specialized transport carriers is a key event in the mechanisms of polarized sorting. In some cases this process is mediated by recognition of sorting signals in the cytosolic tails of the proteins by components of protein coats associated with the cytosolic face of the donor compartment. One of the best-documented examples is the sorting of various transmembrane proteins to the somatodendritic domain...

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“…In general, tethering factors can be divided into two major groups: elongated coiled-coil proteins and multisubunit tethering complexes (MTCs) (Bröcker et al, 2010;Sztul and Lupashin, 2006;Whyte and Munro, 2002;Yu and Hughson, 2010). Tethers often cooperate with Rab small GTPases, SNAREs and vesicle coats, and are thought to be involved in vesicular capturing and docking to specific target membranes (Angers and Merz, 2011;Cai et al, 2007). The involvement of tethering factors in vesicular recognition and targeting, and their contribution to membrane fusion specificity have been proposed by numerous studies (Sztul and Lupashin, 2006).…”

Section: Introductionmentioning

confidence: 99%

The COG complex interacts with multiple Golgi SNAREs and enhances fusogenic SNARE complexes assembly

Laufman

Hong

Lev

2013

Journal of Cell Science

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SummaryMultisubunit tethering complexes (MTCs) positively regulate vesicular fusion by as yet unclear mechanism. In this study we provide evidence that the MTC COG enhances the assembly of fusogenic Golgi SNARE complexes and concomitantly prevents nonfusogenic tSNARE interactions. This capability is possibly mediated by multiple direct interactions of COG subunits and specific Golgi SNAREs and SM (Sec1/Munc18) proteins. By using a systematic co-immunoprecipitation analysis, we identified seven new interactions between the COG subunits and components of the Golgi fusion machinery in mammalian cells. Our studies suggest that these multivalent interactions are critical for the assembly of fusogenic SNARE complexes on the Golgi apparatus and consequently for facilitating endosome-to-trans-Golgi network (TGN) and intra-Golgi retrograde transport, and also for coordinating these transport routes.

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New links between vesicle coats and Rab-mediated vesicle targeting

Cited by 68 publications

References 144 publications

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

Rab5 and its effector FHF contribute to neuronal polarity through dynein-dependent retrieval of somatodendritic proteins from the axon

The COG complex interacts with multiple Golgi SNAREs and enhances fusogenic SNARE complexes assembly

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