The neurotoxins 2,5‐hexanedione and acrylamide promote aggregation of intermediate filaments in cultured fibroblasts

Durham, Heather D.; Pena, Sérgio D.J.; Carpenter, Stirling

doi:10.1002/mus.880060903

Cited by 76 publications

(36 citation statements)

References 20 publications

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“…3F). Consistent with literature reports (20,47), actin stress fiber disassembly but no microtubule depolymerization was detected in ACR-treated cells (data not shown). As the emergence of nuclear folds has been described to occur in some vimentin null cells, in cells expressing vimentin mutants or containing thick IF bundles, and in ACRtreated neurons (33,43,76,78), we used the percentage of cells with nuclear invaginations as an estimate of the extent of IF disruption.…”

Section: Viral Entry Does Not Alter Vimentin If Structuresupporting

confidence: 93%

“…ACR treatment of HF induced cell rounding and contraction, accompanied by the aggregation of vimentin IF in elongated bundles extending into the cells' retraction fibers (Fig. 3A to E) (2,20) and by the appearance of invaginations or folds in the nuclear envelope (Fig. 3F).…”

Section: Viral Entry Does Not Alter Vimentin If Structurementioning

confidence: 99%

“…To determine whether the integrity of the vimentin cytoskeleton is required to facilitate the onset of viral infection, HF were treated with a 5 mM ACR solution for 2, 4, 6, or 8 h prior to infection with either AD169 or TB40/E. ACR is a neurotoxin that has been extensively used to disrupt the organization of IF in neurons and in other cells types (2,20,21,33,75). ACR treatment of HF induced cell rounding and contraction, accompanied by the aggregation of vimentin IF in elongated bundles extending into the cells' retraction fibers (Fig.…”

Section: Viral Entry Does Not Alter Vimentin If Structurementioning

confidence: 99%

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Onset of Human Cytomegalovirus Replication in Fibroblasts Requires the Presence of an Intact Vimentin Cytoskeleton

Miller

Hertel

2009

J Virol

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Like all viruses, herpesviruses extensively interact with the host cytoskeleton during entry. While microtubules and microfilaments appear to facilitate viral capsid transport toward the nucleus, evidence for a role of intermediate filaments in herpesvirus entry is lacking. Here, we examined the function of vimentin intermediate filaments in fibroblasts during the initial phase of infection of two genotypically distinct strains of human cytomegalovirus (CMV), one with narrow (AD169) and one with broad (TB40/E) cell tropism. Chemical disruption of the vimentin network with acrylamide, intermediate filament bundling in cells from a patient with giant axonal neuropathy, and absence of vimentin in fibroblasts from vimentin ؊/؊ mice severely reduced entry of either strain. In vimentin null cells, viral particles remained in the cytoplasm longer than in vimentin ؉/؉ cells. TB40/E infection was consistently slower than that of AD169 and was more negatively affected by the disruption or absence of vimentin. These findings demonstrate that an intact vimentin network is required for CMV infection onset, that intermediate filaments may function during viral entry to facilitate capsid trafficking and/or docking to the nuclear envelope, and that maintenance of a broader cell tropism is associated with a higher degree of dependence on the vimentin cytoskeleton. viduals (8, 58). Virtually all cell types, with the exception of lymphocytes and polymorphonuclear leukocytes, can support CMV replication in vivo (80), and this remarkably broad tropism is at the basis of the numerous clinical manifestations of CMV infection (8, 58). The range of permissive cells in vitro is more limited, with human fibroblasts (HF) and endothelial cells being the most widely used for propagation of clinical isolates. Two extensively studied strains, AD169 and Towne, were generated by serial passage of tissue isolates in HF for the purpose of vaccine development (22,68). During this process, both strains accumulated numerous genomic changes (11) and lost the ability to grow in cell types other than HF. By contrast, propagation in endothelial cells produced strains with more intact genomes and tropism, such as TB40/E, VR1814, TR, and PH (59, 80). Human cytomegalovirus (CMV) is a ubiquitous herpesvirus that can cause serious disease in immunocompromised indiThe viral determinants of endothelial and epithelial cell tropism have recently been mapped to the UL128-UL131A (UL128-131A) genomic locus (32,92,93). Each of the products of the UL128, UL130, and UL131A genes is independently required for tropism and participates in the formation of a complex at the surface of the virion with the viral glycoproteins gH and gL (74, 93), which can also independently associate with gO (45). The gH/gL/UL128-131A complex appears to be required for entry into endothelial cells by endocytosis, followed by low-pH-dependent fusion of the virus envelope with endosomal membranes (73, 74) although some virus strains expressing the UL128-UL131A genes do not require endosome acid...

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Section: Viral Entry Does Not Alter Vimentin If Structuresupporting

confidence: 93%

Section: Viral Entry Does Not Alter Vimentin If Structurementioning

confidence: 99%

Section: Viral Entry Does Not Alter Vimentin If Structurementioning

confidence: 99%

See 1 more Smart Citation

Onset of Human Cytomegalovirus Replication in Fibroblasts Requires the Presence of an Intact Vimentin Cytoskeleton

Miller

Hertel

2009

J Virol

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“…The presence of a similar longitudinal redistribution of NF strongly suggests that NF transport is accelerated also in the inherited giant axonal neuropathy. Moreover, disorganization of fibroblast IF has been observed in 2,5-HxD intoxication, suggesting that the effect of this compound involves other types of IF also (50). The elucidation of the precise effect of 2,5-HxD on IF may therefore provide important insight in the genetic defect responsible for the inherited forms of giant axonal neuropathy.…”

Section: A3mentioning

confidence: 99%

Giant axonal neuropathy: acceleration of neurofilament transport in optic axons.

Monaco¹,

Autilio-Gambetti²,

Zabel³

et al. 1985

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

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Giant axonal neuropathies are a group of acquired and inherited human diseases morphologically characterized by accumulation of neurofilaments (NF) in enlargements of preterminal regions of central and peripheral axons. Slow axonal transport was studied in the optic systems of rats treated with 2,5-hexanedione, a toxic compound that produces an experimental model of giant axonal neuropathy. The transport rate of NF and of two other polypeptides of Mr 64,000 and 62,000 were selectively increased. Other components of the slow axonal transport were not affected. Acceleration of labeled NF was also observed when 2,5-hexanedione was given after [35S~methionine administration. Morphometric analysis revealed that the number of NF and the axon size were decreased in regions of optic axons proximal to the enlargements. It is suggested that acceleration of NF transport leads to a longitudinal redistribution of NF: NF decrease proximally and increase distally, forming NF-containing enlargements. Evidence was obtained that polypeptides of Mr 64,000 and 62,000 are cytoskeletal components related to intermediate filaments, normally migrating with the component a of the slow axonal transport. The 2,5-hexanedione axon may provide insight into the pathogenesis of inherited and acquired giant axonal neuropathies and offers a model to investigate the relationship between number of NF and axonal size in central axons.Axonal transport involves the migration of highly ordered complexes of proteins at five distinct rates (1). In mammalian optic axons two groups of proteins, slow component a (SCa) and slow component b (SCb), have transport rates of 0.3 mm/day and 2-3 mm/day, respectively (2). SCa comprises neurofilaments (NF), tubulin, and microtubule-associated proteins, whereas SCb carries over 200 polypeptides, including actin, calmodulin, neuronal-specific enolase, and creatine kinase (3).The use of experimental models has added new insight to the role that disturbances of the axonal transport play in the pathophysiology of human diseases of the central and peripheral nervous systems.Giant axonal neuropathies are a group of diseases comprising toxic as well as inherited conditions (4, 5). The pathological hallmark of these diseases is the presence of masses of NF producing focal enlargements in the preterminal regions of axons. In advanced stages of the neuropathy, the enlargements extend proximally and the distal part of the involved axons eventually undergoes degeneration in several central and peripheral axonal pathways. However, in experimental models no degeneration has been observed in the primary optic pathway despite the presence of numerous enlarged axons (6-8).Methyl n-butyl ketone, n-hexane, and their metabolite 2,5-hexanedione (2,5-HxD) (9, 10) are toxic agents that cause distal giant axonopathies. Methyl n-butyl ketone and n-hexane are widely used as solvents and have caused outbreaks of polyneuropathies among industrial workers (11, 12) and in individuals intentionally inhaling glue vapors (13). The distal gi...

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“…A number of other small-molecular-weight compounds have also been found to affect cIF organization. These include triethyl lead chloride [Zimmerman et al, 19861, the hexacarbon solvent 2,5-hexanedione [Durham et al, 1983;Durham, 19881, carbon disulfide [Pappolla et al, 19871, acrylamide [Durham et al, 1983;Eckert, 1985;Sager and Matheson, 1988;Klymkowsky, 19881, inhibitors of energy metabolism [Maro and Bornens, 1982;Klymkowsky, 19881, inhibitors of protein synthesis [Sharpe et al, 1980;Klymkowsky, 19881, the amino acid analogue L-azetindine-2-carboxylic acid [Thomas et al, 1982;Klymkowsky, 19881, p,p'-iminodipropionitrile [Clark et al, 1980;Papasozomenos et al, 1981;Griffin et al, 19831, nickel [Katsuma et al, 19871, and the nucleoside analogue cordycepin [Zeive and Roemer, 19881. All cause the collapse of cIFs organization without obvious effects on microtubule organization.…”

Section: New Drugsmentioning

confidence: 99%

Functions of intermediate filaments

Klymkowsky

Bachant

Domingo

1989

Cell Motil. Cytoskeleton

179

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The neurotoxins 2,5‐hexanedione and acrylamide promote aggregation of intermediate filaments in cultured fibroblasts

Cited by 76 publications

References 20 publications

Onset of Human Cytomegalovirus Replication in Fibroblasts Requires the Presence of an Intact Vimentin Cytoskeleton

Onset of Human Cytomegalovirus Replication in Fibroblasts Requires the Presence of an Intact Vimentin Cytoskeleton

Giant axonal neuropathy: acceleration of neurofilament transport in optic axons.

Functions of intermediate filaments

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