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

Journal Article · Thu May 01 04:00:00 EDT 2008 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2007.12.026· OSTI ID:21140830

Song, Changcheng ^[1]; Zhen, Xiao ^[2]; Nagashima, Kunio ^[3]; Li, Chou-Chi H ^[1]; Lockett, Stephen J ^[3]; Renming, Dai ^[1]; Cho, Edward H ^[3]; Conrads, Thomas P; Veenstra, Timothy D ^[4]; Colburn, Nancy H; Qing, Wang ^[5]; Jiming, Wang ^[6]

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1. Laboratory of Cancer Prevention, Basic Research Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702 (United States)
2. Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702 (United States)
3. Image Analysis Laboratory, Advanced Technology Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702 (United States)
4. Lab. of Proteomics and Analytical Technologies, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702 (United States)
5. Lab. of Cancer Prevention, Basic Research Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702 (United States)
6. Lab. of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702 (United States)

Cadmium (Cd{sup 2+}) is a heavy metal ion known to have a long biological half-life in humans. Accumulating evidence shows that exposure to Cd{sup 2+} is associated with neurodegenerative diseases characterized by the retention of ubiquitinated and misfolded proteins in the lesions. Here, we report that Cd{sup 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{sup 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{sup 2+} indicates that the C-terminal tail (no. 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{sup 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{sup 2+} toxicity and associated diseases.

• OSTI ID: 21140830
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 228; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BIOLOGICAL HALF-LIFE
CADMIUM
CADMIUM IONS
CELL CONSTITUENTS
DETERGENTS
HEAVY METALS
INHIBITION
MUTANTS
NERVOUS SYSTEM DISEASES
PROTEINS
RETENTION
TOXICITY