Interference with ubiquitination causes oxidative damage and increased protein nitration: implications for neurodegenerative diseases
Interference with ubiquitination causes oxidative damage and increased protein nitration: implications for neurodegenerative diseases
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DOI：
10.1111/j.1471-4159.2004.02493.x
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发表时间：
2004-07-01
影响因子：
4.7
通讯作者：
Jenner, P
中科院分区：
文献类型：
--
作者：
Hyun, DH;Gray, DA;Jenner, P
抑制降解异常蛋白质的蛋白酶体途径可导致蛋白质聚集、氧化损伤增加和蛋白质硝化增加。我们现在表明干扰多泛素化也有类似的后果。在NT-2和SK-N-MC细胞中表达显性阴性突变型泛素（K48R）导致细胞生长速率下降，氧化损伤（蛋白质羰基和脂质过氧化）增加，一氧化氮产生和蛋白质硝化升高。它还使细胞对4-羟基-2,3-反式壬烯醛高度敏感，壬烯醛是脂质过氧化、过氧化氢和生长因子剥夺的神经毒性终产物。过表达野生型泛素不产生这些影响。我们的数据表明，在不同的点上和通过不同的机制干扰泛素-蛋白酶体途径可以产生许多人类神经退行性疾病的共同特征，如脂质过氧化，蛋白质氧化和蛋白质硝化增加。我们认为，这一通路在多个点上的缺陷可能产生神经退行性疾病的共同特征，并且更多这样的缺陷仍有待发现。
Inhibition of the proteasomal pathway for degrading abnormal proteins leads to protein aggregation, increased oxidative damage and increased protein nitration. We now show that interference with polyubiquitination has similar consequences. Expression of a dominant-negative mutant form of ubiquitin (K48R) in NT-2 and SK-N-MC cells caused decreased cell growth rates and increased oxidative damage (protein carbonyls and lipid peroxidation), nitric oxide production and elevated protein nitration. It also rendered cells highly sensitive to 4-hydroxy-2,3-trans-nonenal, a neurotoxic end-product of lipid peroxidation, hydrogen peroxide and deprivation of growth factors. Overexpression of wild-type ubiquitin did not produce these effects. Our data show that interference with the ubiquitin-proteasome pathway at a different point and by a different mechanism can produce many of the common features of human neurodegenerative diseases, such as increased lipid peroxidation, protein oxidation and protein nitration. We suggest that defects in this pathway at multiple points could produce the common features of neurodegenerative diseases, and that more such defects remain to be discovered.