Golgi fragmentation is Rab and SNARE dependent in cellular models of Parkinson’s disease

Rendón, Wilson O.; Martínez‐Alonso, Emma; Tomàs, Mariona; Martínez-Martínez, Narcisa; Martı́nez-Menárguez, José A.

doi:10.1007/s00418-012-1059-4

Cited by 71 publications

(71 citation statements)

References 35 publications

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“…Re-expression of Rab8B SR or Rab29 SR in the respective knockdown cells, however, did not restore the compacted Golgi at all (Fig. 3, A and B) despite the fact that involvement of Rab8 and Rab29 in Golgi morphology had been reported by other groups (15,17). The Rab8B and Rab29 siRNAs used in this study may also reduce the expression level of some other unrelated molecule(s) that is required for the compacted Golgi morphology.…”

Section: Resultsmentioning

confidence: 54%

Small GTPase Rab2B and Its Specific Binding Protein Golgi-associated Rab2B Interactor-like 4 (GARI-L4) Regulate Golgi Morphology

Aizawa

Fukuda

2015

Journal of Biological Chemistry

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Background: Rab small GTPases are membrane trafficking proteins in eukaryotes. Results: Comprehensive knockdown screening identified six Rab isoforms that are involved in regulating Golgi morphology in HeLa-S3 cells. Conclusion: Five of the six Rabs, including Rab2A and Rab2B, non-redundantly regulate Golgi morphology. A Rab2B-specific effector, GARI-L4, also regulates it. Significance: This is the first study to systematically analyze all human Rabs in the Golgi.

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Section: Resultsmentioning

confidence: 54%

Small GTPase Rab2B and Its Specific Binding Protein Golgi-associated Rab2B Interactor-like 4 (GARI-L4) Regulate Golgi Morphology

Aizawa

Fukuda

2015

Journal of Biological Chemistry

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“…The Rab GTPase Rab8a, which showed the strongest rescue of αS-toxicity in the nematode PD model (Gitler et al, 2008), is associated with recycling endosomes and basolateral trafficking events from the trans-Golgi network to the plasma membrane (Henry and Sheff, 2008). Also, Golgi fragmentation was recently shown to be Rab and SNARE dependent in cellular models of PD, further linking Rab8 with αS (Rendon et al, 2013). Although the genetic variant A30P αS has been observed to co-precipitate with Rab8 in transgenic mice (Dalfo et al, 2004b), no direct interaction between Rab8a, or any other Rab GTPase, with αS has been reported thus far.…”

Section: Discussionmentioning

confidence: 98%

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Yin¹,

Fonseca²,

Eisbach³

et al. 2014

Neurobiology of Disease

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Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 -the Drosophila ortholog of Rab8a -ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS-Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction.

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“…For example, a single amino acid substitution of a phosphorylated residue on the yeast homologue Sed5 resulted in the normally dispersed yeast Golgi apparatus to form an ordered structure similar to the mammalian Golgi apparatus (21). Interestingly, another study showed that STX5 levels affected Golgi apparatus order in the presence of a drug that fragments the Golgi apparatus (22). STX5 is also linked to rebuilding Golgi apparatus morphology following mitosis.…”

Section: Discussionmentioning

confidence: 99%

Potent Inhibition of Human Cytomegalovirus by Modulation of Cellular SNARE Syntaxin 5

Cruz

Streck

Ferguson

et al. 2017

J Virol

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Formation of the cytoplasmic viral assembly compartment (cVAC) is an important step for efficient human cytomegalovirus (HCMV) assembly. To do this, the virus must alter and repurpose the normal cellular balance of membrane and protein flux, a process that is not well understood. Although a recent screen identified three viral proteins essential for cVAC formation, less is known about the contribution of cellular factors. We show that HCMV infection increases the protein level of a cellular trafficking factor, syntaxin 5 (STX5), a member of the syntaxin family of SNARE proteins. STX5 is recruited to the cVAC in infected cells and is required for the efficient production of infectious virions. We find that STX5 is important for normal cVAC morphology and the proper localization of viral proteins. A previously identified inhibitor of trafficking, Retro94, causes the mislocalization of STX5, an altered cVAC morphology, and dispersal of viral proteins. The presence of Retro94 results in severely impaired production of infectious virions, with a decrease as great as 5 logs. We show that this inhibition is conserved among different strains of HCMV and the various cell types that support infection, as well as for murine CMV. Thus, our data identify a key cellular trafficking factor important for supporting HCMV infection.IMPORTANCE Human cytomegalovirus (HCMV) infection causes severe disease and mortality in immunocompromised individuals, including organ transplant and AIDS patients. In addition, infection of a developing fetus may result in lifelong complications such as deafness and learning disabilities. Understanding in detail the processes involved in HCMV replication is important for developing novel treatments. One of these essential processes, assembly of infectious virions, takes places in the cytoplasmic viral assembly compartment. We identify a cellular protein, syntaxin 5, important for generating this compartment, and show that it is required for the efficient production of infectious virions. We also show that a small molecule that disrupts this protein also significantly reduces the amount of infectious virions that are generated. Thus, by pinpointing a cellular protein that is important in the replication cycle of HCMV, we identified a novel target that can be pursued for therapeutic intervention.

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Golgi fragmentation is Rab and SNARE dependent in cellular models of Parkinson’s disease

Cited by 71 publications

References 35 publications

Small GTPase Rab2B and Its Specific Binding Protein Golgi-associated Rab2B Interactor-like 4 (GARI-L4) Regulate Golgi Morphology

Small GTPase Rab2B and Its Specific Binding Protein Golgi-associated Rab2B Interactor-like 4 (GARI-L4) Regulate Golgi Morphology

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Potent Inhibition of Human Cytomegalovirus by Modulation of Cellular SNARE Syntaxin 5

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