Arsenic Compromises Both p97 and Proteasome Functions

Joseph Tillotson, Christopher J. Zerio, Bryan Harder, Andrew J. Ambrose, Kevin S. Jung, Minjin Kang, Donna D. Zhang, Eli Chapman

Research output: Research - peer-reviewArticle

Abstract

Exposure to arsenic is a worldwide problem that affects more than 200 million people. The underlying mechanisms of arsenic toxicity have been difficult to ascertain due to arsenic's pleotropic effects. A number of recent investigations have shown that arsenic can compromise protein quality control through the ubiquitin proteasome system (UPS) or the endoplasmic reticulum associated protein degradation (ERAD) pathway. In this article, a link between arsenic and protein quality control is reported. Biochemical and cellular data demonstrate a misregulation of the ATPase cycle of the ATPase associated with various cellular activities (AAA+) chaperone, p97. Interestingly, the loss of p97 activity is due to the increased rate of ATP hydrolysis, which mimics a collection of pathogenic genetic p97 lesions. Cellular studies, using a well characterized reporter of both the proteasome and p97, show the proteasome to also be compromised. This loss of both p97 and proteasome functions can explain the catastrophic protein quality control issues observed in acute, high level arsenic exposures.

LanguageEnglish (US)
Pages1508-1514
Number of pages7
JournalChemical Research in Toxicology
Volume30
Issue number7
DOIs
StatePublished - Jul 17 2017

Fingerprint

Arsenic
Proteasome Endopeptidase Complex
Proteins
Quality Control
Quality control
Adenosine Triphosphatases
Endoplasmic Reticulum-Associated Degradation
Ubiquitin
Proteolysis
Hydrolysis
Adenosine Triphosphate
Toxicity
Degradation

ASJC Scopus subject areas

  • Toxicology

Cite this

Tillotson, J., Zerio, C. J., Harder, B., Ambrose, A. J., Jung, K. S., Kang, M., ... Chapman, E. (2017). Arsenic Compromises Both p97 and Proteasome Functions. Chemical Research in Toxicology, 30(7), 1508-1514. DOI: 10.1021/acs.chemrestox.7b00158

Arsenic Compromises Both p97 and Proteasome Functions. / Tillotson, Joseph; Zerio, Christopher J.; Harder, Bryan; Ambrose, Andrew J.; Jung, Kevin S.; Kang, Minjin; Zhang, Donna D.; Chapman, Eli.

In: Chemical Research in Toxicology, Vol. 30, No. 7, 17.07.2017, p. 1508-1514.

Research output: Research - peer-reviewArticle

Tillotson, J, Zerio, CJ, Harder, B, Ambrose, AJ, Jung, KS, Kang, M, Zhang, DD & Chapman, E 2017, 'Arsenic Compromises Both p97 and Proteasome Functions' Chemical Research in Toxicology, vol 30, no. 7, pp. 1508-1514. DOI: 10.1021/acs.chemrestox.7b00158
Tillotson J, Zerio CJ, Harder B, Ambrose AJ, Jung KS, Kang M et al. Arsenic Compromises Both p97 and Proteasome Functions. Chemical Research in Toxicology. 2017 Jul 17;30(7):1508-1514. Available from, DOI: 10.1021/acs.chemrestox.7b00158
Tillotson, Joseph ; Zerio, Christopher J. ; Harder, Bryan ; Ambrose, Andrew J. ; Jung, Kevin S. ; Kang, Minjin ; Zhang, Donna D. ; Chapman, Eli. / Arsenic Compromises Both p97 and Proteasome Functions. In: Chemical Research in Toxicology. 2017 ; Vol. 30, No. 7. pp. 1508-1514
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