A novel role for ATM in regulating proteasome- mediated protein degradation through suppression of the ISG15 conjugation pathway

Laurence M. Wood, Surendran Sankar, Ryan E. Reed, Arthur L. Haas, Leroy-Fong Liu, Peter McKinnon, Shyamal D. Desai

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Ataxia Telangiectasia (A-T) is an inherited immunodeficiency disorder wherein mutation of the ATM kinase is responsible for the A-T pathogenesis. Although the precise role of ATM in A-T pathogenesis is still unclear, its function in responding to DNA damage has been well established. Here we demonstrate that in addition to its role in DNA repair, ATM also regulates proteasome-mediated protein turnover through suppression of the ISG15 pathway. This conclusion is based on three major pieces of evidence: First, we demonstrate that proteasome-mediated protein degradation is impaired in A-T cells. Second, we show that the reduced protein turnover is causally linked to the elevated expression of the ubiquitin-like protein ISG15 in A-T cells. Third, we show that expression of the ISG15 is elevated in A-T cells derived from various A-T patients, as well as in brain tissues derived from the ATM knockout mice and A-T patients, suggesting that ATM negatively regulates the ISG15 pathway. Our current findings suggest for the first time that proteasome-mediated protein degradation is impaired in A-T cells due to elevated expression of the ISG15 conjugation pathway, which could contribute to progressive neurodegeneration in A-T patients.

Original languageEnglish
Article numbere16422
JournalPLoS One
Volume6
Issue number1
DOIs
Publication statusPublished - 2011
Externally publishedYes

Fingerprint

Ataxia Telangiectasia
proteasome endopeptidase complex
Automatic teller machines
Proteasome Endopeptidase Complex
protein degradation
Proteolysis
Degradation
Cells
protein metabolism
Proteins
pathogenesis
cells
Ubiquitins
immunosuppression
ubiquitin
DNA repair
DNA damage
DNA
phosphotransferases (kinases)
Brain

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

A novel role for ATM in regulating proteasome- mediated protein degradation through suppression of the ISG15 conjugation pathway. / Wood, Laurence M.; Sankar, Surendran; Reed, Ryan E.; Haas, Arthur L.; Liu, Leroy-Fong; McKinnon, Peter; Desai, Shyamal D.

In: PLoS One, Vol. 6, No. 1, e16422, 2011.

Research output: Contribution to journalArticle

Wood, Laurence M. ; Sankar, Surendran ; Reed, Ryan E. ; Haas, Arthur L. ; Liu, Leroy-Fong ; McKinnon, Peter ; Desai, Shyamal D. / A novel role for ATM in regulating proteasome- mediated protein degradation through suppression of the ISG15 conjugation pathway. In: PLoS One. 2011 ; Vol. 6, No. 1.
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