Role of Rab1b in COPII dynamics and function

Slavin, Ileana; García, Iris Alejandra; Monetta, Pablo Miguel; Martinez, Hernán; Roméro, N.; Álvarez, Cecilia

doi:10.1016/j.ejcb.2010.10.001

Cited by 25 publications

(30 citation statements)

References 50 publications

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“…Indeed, we detected inhibition of autophagosome-lysosome fusion in cells expressing mSOD1, consistent with this notion. Rab1 is multi-tasking protein in ER-Golgi transport, mediating recruitment of cargo into COPII vesicles, regulation of COPII dynamics and function, transport between ER and ERGIC, and ERGIC and Golgi, recruitment of kinesin and dynein to microtubules, and microtubule organisation and function [27,61,63]. Previous studies have demonstrated that loss of Rab1 function prevents incorporation of secretory cargo into COPII vesicles [21] and leads to abnormal microtubules [61].…”

Section: Discussionmentioning

confidence: 98%

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Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

et al. 2015

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Several diverse proteins are linked genetically/pathologically to neurodegeneration in amyotrophic lateral sclerosis (ALS) including SOD1, TDP-43 and FUS. Using a variety of cellular and biochemical techniques, we demonstrate that ALS-associated mutant TDP-43, FUS and SOD1 inhibit protein transport between the endoplasmic reticulum (ER) and Golgi apparatus in neuronal cells. ER-Golgi transport was also inhibited in embryonic cortical and motor neurons obtained from a widely used animal model (SOD1(G93A) mice), validating this mechanism as an early event in disease. Each protein inhibited transport by distinct mechanisms, but each process was dependent on Rab1. Mutant TDP-43 and mutant FUS both inhibited the incorporation of secretory protein cargo into COPII vesicles as they bud from the ER, and inhibited transport from ER to the ER-Golgi intermediate (ERGIC) compartment. TDP-43 was detected on the cytoplasmic face of the ER membrane, whereas FUS was present within the ER, suggesting that transport is inhibited from the cytoplasm by mutant TDP-43, and from the ER by mutant FUS. In contrast, mutant SOD1 destabilised microtubules and inhibited transport from the ERGIC compartment to Golgi, but not from ER to ERGIC. Rab1 performs multiple roles in ER-Golgi transport, and over-expression of Rab1 restored ER-Golgi transport, and prevented ER stress, mSOD1 inclusion formation and induction of apoptosis, in cells expressing mutant TDP-43, FUS or SOD1. Rab1 also co-localised extensively with mutant TDP-43, FUS and SOD1 in neuronal cells, and Rab1 formed inclusions in motor neurons of spinal cords from sporadic ALS patients, which were positive for ubiquitinated TDP-43, implying that Rab1 is misfolded and dysfunctional in sporadic disease. These results demonstrate that ALS-mutant forms of TDP-43, FUS, and SOD1 all perturb protein transport in the early secretory pathway, between ER and Golgi compartments. These data also imply that restoring Rab1-mediated ER-Golgi transport is a novel therapeutic target in ALS.

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Section: Discussionmentioning

confidence: 98%

“…Rab1 regulates ER-Golgi transport, including COPII vesicle budding, delivery, tethering, fusion to the Golgi [47,56] and COPII function [63]. In yeast, the Rab1 homologue Ypt1 also mediates microtubule organisation and function, and loss of Ypt1 function results in microtubule defects [61].…”

Section: Introductionmentioning

confidence: 99%

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

et al. 2015

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“…By comparison, the patients we studied were substantially more similar to those with a complicated form of HSP known as SPOAN (25). Analysis of the genes within this region revealed the presence of at least three that are known to function in ER morphogenesis: RAB1B (a Rab-type GTPase required for vesicle secretion from the ER), YIF1A (a transmembrane protein also implicated in the early secretory pathway), and RTN3 (a member of the reticulon family of ER shaping proteins) (49)(50)(51). Sequence analysis of these genes in patients with SPOAN will be enlightening, and may help to confirm a specific requirement for secretory transport from the ER in maintenance of neuronal integrity.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure

Beetz

Johnson

Schuh

et al. 2013

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

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Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of gait disorders. Their pathological hallmark is a length-dependent distal axonopathy of nerve fibers in the corticospinal tract. Involvement of other neurons can cause additional neurological symptoms, which define a diverse set of complex hereditary spastic paraplegias. We present two siblings who have the unusual combination of early-onset spastic paraplegia, optic atrophy, and neuropathy. Genome-wide SNP-typing, linkage analysis, and exome sequencing revealed a homozygous c.316C>T (p.R106C) variant in the Trk-fused gene (TFG) as the only plausible mutation. Biochemical characterization of the mutant protein demonstrated a defect in its ability to self-assemble into an oligomeric complex, which is critical for normal TFG function. In cell lines, TFG inhibition slows protein secretion from the endoplasmic reticulum (ER) and alters ER morphology, disrupting organization of peripheral ER tubules and causing collapse of the ER network onto the underlying microtubule cytoskeleton. The present study provides a unique link between altered ER architecture and neurodegeneration.membrane trafficking | COPII-mediated secretion | ER exit site H ereditary spastic paraplegias (HSPs) are a diverse group of disorders characterized by spastic weakness in the lower extremities, which results from degeneration of upper motoneuron axons in the corticospinal tract (1, 2). Based on the presence or absence of other neurological abnormalities, HSPs are classified as complicated or pure, respectively. In addition to lower-limb spasticity, complicated forms of HSP may be associated with ataxia, mental retardation, dementia, extrapyramidal signs, visual dysfunction, and/or epilepsy. HSPs are typically progressive, but age of onset is highly variable. The heterogeneity in clinical presentation is accompanied by genetic heterogeneity. To date, more than 40 different genetic loci, which include nearly all modes of inheritance, have been linked to HSPs (1-5). However, in nearly half of these cases, the identities of the causative genes remain unknown. The identification of additional HSP genes and, more importantly, the functional characterization of their encoded products, will both contribute to our understanding of the pathomechanisms underlying HSPs and reveal the general requirements for lifelong axonal maintenance.More than half the HSP cases in North America and Northern Europe can be attributed to defects in organelle dynamics (6). In particular, mutations that impact the architecture of the endoplasmic reticulum (ER) are common in patients with HSP. The ER is comprised of a network of membrane tubules and sheetlike cisternae that extend throughout the cytoplasm and encase the nucleus (7-9). Several factors contribute to this architecture, including (i) membrane-bending proteins of the REEP and reticulon families; (ii) regulators of the microtubule cytoskeleton, which governs the spatial patterning of the ER network; and (iii) components of the ear...

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“…Rab1a recruitment of the tethering factor p115 into a SNARE complex promotes COPII vesicles budding from the ER for their fusion with Golgi membranes and or recycling Golgi-derived COPI vesicles[88],[89]. It has been shown that Rab1b interacts with the COPII components Sec23, Sec24 and Sec31 and that inhibition of Rab1b changes the COPII phenotype, suggesting a key regulatory role[90]. It has also been shown that Rab1a is associated with early endocytic vesicles and required for their microtubule-based motility[87].…”

Section: Ld-associated Rab Proteinsmentioning

confidence: 99%

Rab proteins implicated in lipid storage and mobilization

Kiss

Nilsson²

2014

J Biomed Res

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Abnormal intracellular accumulation or transport of lipids contributes greatly to the pathogenesis of human diseases. In the liver, excess accumulation of triacylglycerol (TG) leads to fatty liver disease encompassing steatosis, steatohepatitis and fibrosis. This places individuals at risk of developing cirrhosis, hepatocellular carcinoma or hepatic decompensation and also contributes to the emergence of insulin resistance and dyslipidemias affecting many other organs. Excessive accumulation of TG in adipose tissue contributes to insulin resistance as well as to the release of cytokines attracting leucocytes leading to a pro-inflammatory state. Pathological accumulation of cholesteryl ester (CE) in macrophages in the arterial wall is the progenitor of atherosclerotic plaques and heart disease. Overconsumption of dietary fat, cholesterol and carbohydrates explains why these diseases are on the increase yet offers few clues for how to prevent or treat individuals. Dietary regimes have proven futile and barring surgery, no realistic alternatives are at hand as effective drugs are few and not without side effects. Overweight and obesity-related diseases are no longer restricted to the developed world and as such, constitute a global problem. Development of new drugs and treatment strategies are a priority yet requires as a first step, elucidation of the molecular pathophysiology underlying each associated disease state. The lipid droplet (LD), an up to now overlooked intracellular organelle, appears at the heart of each pathophysiology linking key regulatory and metabolic processes as well as constituting the site of storage of both TGs and CEs. As the molecular machinery and mechanisms of LDs of each cell type are being elucidated, regulatory proteins used to control various cellular processes are emerging. Of these and the subject of this review, small GTPases belonging to the Rab protein family appear as important molecular switches used in the regulation of the intracellular trafficking and storage of lipids.

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Role of Rab1b in COPII dynamics and function

Cited by 25 publications

References 50 publications

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure

Rab proteins implicated in lipid storage and mobilization

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