Microtubule network asymmetry in motile cells: Role of Golgi-derived array

Vinogradova, Tatiana M.; Miller, Paul M.; Kaverina, Irina

doi:10.4161/cc.8.14.9074

Cited by 79 publications

(88 citation statements)

References 96 publications

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“…Alternative possibilities, however, warrant investigation. For example, the orientation of the Golgi apparatus may be important because this organelle, which also associates with the PV, can provide microtubule nucleation function (11). The importance of centrosome orientation to the leading edge for directed migration has been controversial because it is not observed in some experimental systems (43)(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

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Coordinate Control of Host Centrosome Position, Organelle Distribution, and Migratory Response by Toxoplasma gondii via Host mTORC2

Wang

Weiss

Orlofsky

2010

Journal of Biological Chemistry

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The invasion of host cells by Toxoplasma gondii is accompanied by a reorganization of host cell structure, in which the host centrosome and Golgi apparatus are localized to the vacuole, and mitochondria, microtubules, and endolysosomes are recruited to the vacuole perimeter. The mechanism and functional significance of this process have not been well defined. Here, we report that the centrosome-vacuole association was abolished in mammalian target of rapamycin complex 2 (mTORC2)-deficient cells, which also displayed a disordered distribution of perivacuolar host mitochondria and lysosomes. Infection of fibroblasts led to stable, mTORC2-dependent activation of Akt, and Akt inhibition mimicked the effect of mTORC2 ablation on centrosome, mitochondria, and lysosome localization. Mobilization of the centrosome by Akt inhibition was abrogated by inhibitors of glycogen synthase kinase 3 (GSK3), implying that the centrosome is constrained to the vacuole through an mTORC2-Akt-GSK3 pathway. Infected cells were incapable of migration in a wounded monolayer model, and this effect was associated with the inability of centrosomes to reorient in the direction of migration. Both migration and centrosome reorientation were fully restored upon ablation of mTORC2. These findings provide the first linkage of host signals to parasite-mediated host cell reorganization and demonstrate migratory suppression as a novel functional consequence of this process that is associated with mTORC2-mediated centrosome constraint.Toxoplasma gondii, the agent of toxoplasmosis and a major cause of AIDS-associated encephalitis, is a ubiquitous protozoan parasite that serves as a model organism for the study of host cell-parasite interaction (1-4). T. gondii readily invades most mammalian cell types and proliferates within a parasitophorous vacuole (PV), 2 whose membrane combines host plasma membrane-and parasite-derived components (5). The PV provides an interface for interaction with the host and serves as a focal point for a remarkable reorganization of host cell architecture. The host centrosome and Golgi become closely associated with the PV, which is tightly wrapped by host microtubules, mitochondria, and endoplasmic reticulum. In addition, host endolysosomes and autophagosomes localize near the vacuole perimeter (6 -9). Mitochondria-PV association is dependent on a parasite secretory product, ROP2, and knockdown of ROP2 results in profound defects in Toxoplasma growth and virulence (10). Apart from ROP2, no host or parasite signal involved in the reorganization process has been identified. Furthermore, apart from mitochondria-PV association, the functional significance of the reorganized host cell architecture remains unknown.The orientation of the centrosome and Golgi is susceptible to regulation in mammalian cells, for example during directional responses to migratory stimuli (11-13). A potential mechanism, then, of parasite-mediated reorganization is the mimicry of host signals that govern the polarization response, resulting in a stable, in...

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Section: Discussionmentioning

confidence: 99%

“…The orientation of the centrosome and Golgi is susceptible to regulation in mammalian cells, for example during directional responses to migratory stimuli (11)(12)(13). A potential mechanism, then, of parasite-mediated reorganization is the mimicry of host signals that govern the polarization response, resulting in a stable, intrinsically polarized state.…”

mentioning

confidence: 99%

Coordinate Control of Host Centrosome Position, Organelle Distribution, and Migratory Response by Toxoplasma gondii via Host mTORC2

Wang

Weiss

Orlofsky

2010

Journal of Biological Chemistry

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“…Independently of its role in directed cell migration, the adequate positioning of centrosome and Golgi has been proposed to reflect the capability of the cell to polarize (Yadav et al, 2009); therefore, lack of polarizing ability is likely to be an important consequence of CCM3 inactivation. The two functions, cell orientation and Golgi assembly, are likely to be related, as the Golgi apparatus needs to disassemble and reassemble to change its position within the cell when the cell undergoes reorientation, and the integrity and position of the Golgi complex are known to be important for this orientation and directed migration (Vinogradova et al, 2009;Yadav et al, 2009). The effects of CCM3 on the Golgi apparatus are also likely to be linked to CCM pathogenesis, as two different clinically important mutants cannot rescue the effects of CCM3 knockdown on the Golgi.…”

Section: Discussionmentioning

confidence: 99%

CCM3/PDCD10 stabilizes GCKIII proteins to promote Golgi assembly and cell orientation

Fidalgo

Fraile

Pires

et al. 2010

Journal of Cell Science

109

128

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SummaryMutations in CCM3/PDCD10 result in cerebral cavernous malformations (CCMs), a major cause of cerebral hemorrhage. Despite intense interest in CCMs, very little is known about the function of CCM3. Here, we report that CCM3 is located on the Golgi apparatus, forming a complex with proteins of the germinal center kinase III (GCKIII) family and GM130, a Golgi-resident protein. Cells depleted of CCM3 show a disassembled Golgi apparatus. Furthermore, in wound-healing assays, CCM3-depleted cells cannot reorient the Golgi and centrosome properly, and demonstrate impaired migration. Golgi disassembly after either depletion of CCM3 or dissociation of CCM3 from the GM130-GCKIII complex is the result of destabilization of GCKIII proteins and dephosphorylation of their substrate, 14-3-3. Significantly, the phenotype induced by CCM3 depletion can be reverted by expression of wild-type CCM3, but not by diseaseassociated mutants. Our findings suggest that Golgi dysfunction and the ensuing abnormalities of cell orientation and migration resulting from CCM3 mutations contribute to CCM pathogenesis.

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“…the reorganization of MTs and cell polarization (Vinogradova et al, 2009), and addition of MT stabilizing agents or knockdown of MT dynamics regulators has previously been shown to reduce cell migration (Grigoriev et al, 1999;Nakano et al, 2010). Confirming our previous results, a significant reduction in cell migration was detected only in cells expressing the hyperactive HSPB1 mutants (R127W and S135F), while cells expressing a CMT-causing HSPB1 mutation without enhanced tubulin binding (T151I) displayed a migration speed similar to cells expressing HSPB1 WT (Fig.…”

Section: Cmt Neuropathy-causing Hspb1 Mutants Show Enhanced Binding Tmentioning

confidence: 99%

Small Heat-Shock Protein HSPB1 Mutants Stabilize Microtubules in Charcot-Marie-Tooth Neuropathy

Almeida-Souza¹,

Asselbergh²,

d’Ydewalle³

et al. 2011

J. Neurosci.

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Mutations in the small heat shock protein HSPB1 (HSP27) are causative for Charcot-Marie-Tooth (CMT) neuropathy. We previously showed that a subset of these mutations displays higher chaperone activity and enhanced affinity to client proteins. We hypothesized that this excessive binding property might cause the HSPB1 mutant proteins to disturb the function of proteins essential for the maintenance or survival of peripheral neurons. In the present work, we explored this hypothesis further and compared the protein complexes formed by wild-type and mutant HSPB1. Tubulin came out as the most striking differential interacting protein, with hyperactive mutants binding more strongly to both tubulin and microtubules. This anomalous binding leads to a stabilization of the microtubule network in a microtubule-associated protein-like manner as reflected by resistance to cold depolymerization, faster network recovery after nocodazole treatment, and decreased rescue and catastrophe rates of individual microtubules. In a transgenic mouse model for mutant HSPB1 that recapitulates all features of CMT, we could confirm the enhanced interaction of mutant HSPB1 with tubulin. Increased stability of the microtubule network was also clear in neurons isolated from these mice. Since neuronal cells are particularly vulnerable to disturbances in microtubule dynamics, this mechanism might explain the neuron-specific CMT phenotype caused by HSPB1 mutations.

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Microtubule network asymmetry in motile cells: Role of Golgi-derived array

Cited by 79 publications

References 96 publications

Coordinate Control of Host Centrosome Position, Organelle Distribution, and Migratory Response by Toxoplasma gondii via Host mTORC2

Coordinate Control of Host Centrosome Position, Organelle Distribution, and Migratory Response by Toxoplasma gondii via Host mTORC2

CCM3/PDCD10 stabilizes GCKIII proteins to promote Golgi assembly and cell orientation

Small Heat-Shock Protein HSPB1 Mutants Stabilize Microtubules in Charcot-Marie-Tooth Neuropathy

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