A Novel Action of Histone Deacetylase Inhibitors in a Protein Aggresome Disease Model

Corcoran, Lisa; Mitchison, Timothy J.; Liu, Qing

doi:10.1016/j.cub.2004.03.003

Cited by 83 publications

(85 citation statements)

References 15 publications

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“…Consistent with this, we found that aggresome formation in Cd 2+ -treated cells was significantly suppressed by the histone deacetylase inhibitor scriptaid (Corcoran et al, 2004) and by the microtubulin depolarizing agent nocodazole (Johnston et al, 1998) (Fig. 8).…”

Section: Vcp Interacts With Hdac6 Through Its C-terminal Tail (#780-806)supporting

confidence: 82%

The heavy metal cadmium induces valosin-containing protein (VCP)-mediated aggresome formation

Song

Xiao

Nagashima

et al. 2008

Toxicology and Applied Pharmacology

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Cadmium (Cd 2+ ) is a heavy metal ion known to have a long biological half-life in humans. Accumulating evidence shows that exposure to Cd 2+ is associated with neurodegenerative diseases characterized by the retention of ubiquitinated and misfolded proteins in the lesions. Here, we report that Cd 2+ directly induces the formation of protein inclusion bodies in cells. The protein inclusion body is an aggresome, a major organelle for collecting ubiquitinated or misfolded proteins. Our results show that aggresomes are enriched in the detergent-insoluble fraction of Cd 2+ -treated cell lysates. Proteomic analysis identified 145 proteins in the aggresome-enriched fractions. One of the proteins is the highly conserved valosin-containing protein (VCP), which has been shown to colocalize with aggresomes and bind ubiquitinated proteins through its N domain (#1-200). Our subsequent examination of VCP's role in the formation of aggresomes induced by Cd 2+ indicate that the C-terminal tail (#780-806) of VCP interacts with histone deacetylase HDAC6, a mediator for aggresome formation, suggesting that VCP participates in transporting ubiquitinated proteins to aggresomes. This function of VCP is impaired by inhibition of the deacetylase activity of HDAC6 or by over-expression of VCP mutants that do not bind ubiquitinated proteins or HDAC6. Our results indicate that Cd 2+ induces the formation of protein inclusion bodies by promoting the accumulation of ubiquitinated proteins in aggresomes through VCP and HDAC6. Our delineation of the role of VCP in regulating cell responses to ubiquitinated proteins has important implications for understanding Cd 2+ toxicity and associated diseases.

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Section: Vcp Interacts With Hdac6 Through Its C-terminal Tail (#780-806)supporting

confidence: 82%

The heavy metal cadmium induces valosin-containing protein (VCP)-mediated aggresome formation

Song

Xiao

Nagashima

et al. 2008

Toxicology and Applied Pharmacology

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“…The HDAC-dependent functions of HDAC6 on aggresome formation cannot, however, be generalized since, in a model for SOD1 mutant aggresome assembly involved in amyotrophic lateral sclerosis, HDAC inhibitors prevented the accumulation of scattered mSOD1 aggregates in aggresomes, but HDAC6 neutralization by tubacin did not inhibit this process. Moreover, trapoxin, an HDAC inhibitor which does not inhibit HDAC6, showed an efficient inhibition of aggresome formation (Corcoran et al, 2004). There are, therefore, yet unknown HDAC-dependent mechanisms involved in the control of aggresome formation.…”

Section: Hdac6: a Therapeutic Target?mentioning

confidence: 99%

HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

et al. 2007

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Histone deacetylase 6 (HDAC6) is a unique enzyme with specific structural and functional features. It is actively or stably maintained in the cytoplasm and is the only member, within the histone deacetylase family, that harbors a full duplication of its deacetylase homology region followed by a specific ubiquitin-binding domain at the C-terminus end. Accordingly, this deacetylase functions at the heart of a cellular regulatory mechanism capable of coordinating various cellular functions largely relying on the microtubule network. Moreover, HDAC6 action as a regulator of the HSP90 chaperone activity adds to the multifunctionality of the protein, and allows us to propose a critical role for HDAC6 in mediating and coordinating various cellular events in response to different stressful stimuli.

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“…Hence, recent studies have indicated that HDAC inhibitors might prove useful in treatment of such neurodegenerative disorders as Huntington's Disease (37)(38)(39), spinal muscular atrophy ( 40 ), amyotrophic lateral sclerosis (41)(42)(43), and experimental autoimmune encephalomyelitis ( 44 ). Amelioration of neurodegenerative conditions such as oxidative stress ( 45 ), and preservation of white by guest, on March 31, 2019 www.jlr.org…”

Section: Cell Culturementioning

confidence: 99%

HDAC inhibitor SAHA normalizes the levels of VLCFAs in human skin fibroblasts from X-ALD patients and downregulates the expression of proinflammatory cytokines in Abcd1/2-silenced mouse astrocytes

Singh

Khan

Singh

2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words peroxisome • very long chain FA • glia • nitric oxide • cytokine • suberoylanilide hydroxamic acid • X-adrenoleukodystrophy X-adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, with an incidence of approximately 1:17,000 ( 1, 2 ). It is a postnatal progressive demyelinating disorder that primarily affects nervous system white matter and axons, the adrenal cortex, and testis ( 3-5 ). The biochemical signature of X-ALD is increased levels of saturated straight-chain very long chain FAs (VLCFAs; >22:0). VLCFA accumulates in all tissues and lipid classes; however, the degree of accumulation is higher in the cholesterol ester and sphingolipid fractions of brain white matter and adrenal cortex ( 6 ). The elevation of VLCFAs is the consequence of reduced VLCFA peroxisomal ␤ -oxidation ( 7 ) and/or increased activity of FA elongases ( 8, 9 ). The ALD gene (ABCD1), identifi ed by positional cloning ( 10 ), encodes a protein that is related to the peroxisomal ATP binding cassette (ABCD) transmembrane transporter proteins ( 11,12 ). The function of the adrenoleukodystrophy protein (ALDP) and its role in VLCFA metabolism and in the pathogenesis of X-ALD is not well understood at present. However, the VLCFA, especially C26:0, has been documented to cause metabolic alterations leading to membrane perturbation, redox imbalance ( 13 ), and changes in membrane lipid composition ( 14-18 ), as well as the induction of infl ammatory mediators in cultured astrocytes ( 19 ). This study was supported in part by grants from the National Institutes of Health (Grants NS-22576, NS-37766, C06 RR-018823, and C06 RR-015455, and VA merit award BX1072-01. Its Abbreviations: ALDP, adrenoleukodystrophy protein; ALDRP, adrenoleukodystrophy-related protein; AMN, adrenomyeloneuropathy; BBB, blood-brain barrier; cALD, cerebral adrenoleukodystrophy; FAME, FA methyl ester; HDAC, histone deacetylase; iNOS, inducible nitric oxide synthase; 5-LOX, 5-lipoxygenase; PA, phenylacetate; PBA, phenylbutyrate; ROS, reactive oxygen species; SAHA, suberoylanilide hydroxamic acid; TNF-␣ , tumor necrosis factor-␣ ; X-ALD, X-adrenoleukodystrophy; VLCFA, very long chain FA.

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A Novel Action of Histone Deacetylase Inhibitors in a Protein Aggresome Disease Model

Cited by 83 publications

References 15 publications

The heavy metal cadmium induces valosin-containing protein (VCP)-mediated aggresome formation

The heavy metal cadmium induces valosin-containing protein (VCP)-mediated aggresome formation

HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

HDAC inhibitor SAHA normalizes the levels of VLCFAs in human skin fibroblasts from X-ALD patients and downregulates the expression of proinflammatory cytokines in Abcd1/2-silenced mouse astrocytes

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