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.
Highlights
Ataxia Telangiectasia (A-T) (Boder-Sedgwick/Louis-Bar syndrome) is an inherited immunodeficiency disorder with a prevalence rate of 1 in 30,000–100,000 births [1,2,3]
The reduced protein turnover in A-T cells is associated with elevated expression of ISG15
To test whether like other neurodegenerating diseases, the defective ubiquitin-mediated degradation of cellular proteins contributes to neurodegeneration in A-T, we monitored the rate of degradation of overall cellular polyubiquitylated proteins in FT169A (A-T) (ATM null) and FT169A (ATM+) (ATM reconstituted FT169A) isogenic cells [43] using the protein synthesis inhibitor cycloheximide (CHX) [44]
Summary
Ataxia Telangiectasia (A-T) (Boder-Sedgwick/Louis-Bar syndrome) is an inherited immunodeficiency disorder with a prevalence rate of 1 in 30,000–100,000 births [1,2,3]. A-T patients are characterized by pronounced facial spider veins (telangiectsia), recurrent sinopulmonary infections, and an irregular gait (ataxia) that results from progressive neuronal dysfunction [4]. These clinical presentations, which are secondary to sensitivity to ionizing radiation and a marked predisposition to cancer, were explicated in 1995 by Savitsky et al as an autosomal recessive mutation in the Ataxia Telangiectasia Mutated (ATM) gene. ATM is a 370 kDa nuclear Ser/Thr kinase that contributes to the regulation of p53, BRCA1, and Chk signaling pathways, amongst others. The central role of ATM in cell regulation suggests that a loss of function mutations in the ATM gene should result in broadly pleiotropic effects
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