Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2011 Jan 26;6(1):e16422. doi: 10.1371/journal.pone.0016422.
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.
毛细血管扩张性共济失调症（A-T）是一种遗传性免疫缺陷病，ATM 激酶的突变是导致 A-T 发病的原因。尽管 ATM 在 A-T 发病机制中的精确作用仍不清楚，但它在响应 DNA 损伤方面的功能已得到很好的证实。在这里，我们证明 ATM 除了在 DNA 修复中的作用外，还通过抑制 ISG15 途径来调节蛋白酶体介导的蛋白质周转。这一结论基于三个主要证据：首先，我们证明 A-T 细胞中的蛋白酶体介导的蛋白质降解受损。其次，我们表明，降低的蛋白质周转率与 A-T 细胞中上调的泛素样蛋白 ISG15 的表达有因果关系。第三，我们表明，来自各种 A-T 患者的 A-T 细胞以及来自 ATM 敲除小鼠和 A-T 患者的脑组织中，ISG15 的表达升高，表明 ATM 负调节 ISG15 途径。我们目前的发现首次表明，由于 ISG15 缀合途径的表达升高，A-T 细胞中的蛋白酶体介导的蛋白质降解受损，这可能导致 A-T 患者进行性神经退行性变。
