C-terminus of heat shock cognate 70 interacting protein increases following stroke and impairs survival against acute oxidative stress.
C-terminus of heat shock cognate 70 interacting protein increases following stroke and impairs survival against acute oxidative stress.
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DOI：
10.1089/ars.2010.3300
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发表时间：
2011-05
影响因子：
6.6
通讯作者：
Jeannette N. Stankowski;S. Zeiger;Evan L. Cohen;D. DeFranco;Jiyang Cai;B. McLaughlin
中科院分区：
文献类型：
--
作者：
Jeannette N. Stankowski;S. Zeiger;Evan L. Cohen;D. DeFranco;Jiyang Cai;B. McLaughlin
通过热休克蛋白70及其结合伴侣去除或重折叠氧化、变性或错误折叠的蛋白质的决定对于确定病理生理条件下的细胞命运至关重要。HSC70相互作用蛋白（CHIP）的遍在蛋白连接酶C末端的过表达可以弥补其他遍在蛋白连接酶的失败，并增强慢性神经应激下的蛋白质周转和生存。CHIP改变急性神经损伤后细胞命运的能力尚未评估。使用死后人体组织样本，我们提供了第一个证据表明，皮质CHIP表达增加缺血性中风后。体外氧糖剥夺导致蛋白质快速氧化、抗氧化剂消耗、蛋白酶体功能障碍和CHIP表达显著增加。为了确定CHIP上调是否增强神经存活，我们在体外过表达CHIP并在急性氧化应激后24小时评估细胞命运。令人惊讶的是，CHIP过表达的细胞表现更差的抗氧化损伤，积累更多的泛素化和氧化蛋白，并经历了蛋白酶体活性下降。相反，使用小干扰RNA降低原代神经元培养物中CHIP的表达改善了氧化应激后的存活率，这表明在中风样损伤后观察到的CHIP增加可能与存活率降低相关，并且可能对热休克蛋白70的神经保护潜力产生负面影响。
The decision to remove or refold oxidized, denatured, or misfolded proteins by heat shock protein 70 and its binding partners is critical to determine cell fate under pathophysiological conditions. Overexpression of the ubiquitin ligase C-terminus of HSC70 interacting protein (CHIP) can compensate for failure of other ubiquitin ligases and enhance protein turnover and survival under chronic neurological stress. The ability of CHIP to alter cell fate after acute neurological injury has not been assessed. Using postmortem human tissue samples, we provide the first evidence that cortical CHIP expression is increased after ischemic stroke. Oxygen glucose deprivation in vitro led to rapid protein oxidation, antioxidant depletion, proteasome dysfunction, and a significant increase in CHIP expression. To determine if CHIP upregulation enhances neural survival, we overexpressed CHIP in vitro and evaluated cell fate 24 h after acute oxidative stress. Surprisingly, CHIP overexpressing cells fared worse against oxidative injury, accumulated more ubiquitinated and oxidized proteins, and experienced decreased proteasome activity. Conversely, using small interfering RNA to decrease CHIP expression in primary neuronal cultures improved survival after oxidative stress, suggesting that increases in CHIP observed after stroke like injuries are likely correlated with diminished survival and may negatively impact the neuroprotective potential of heat shock protein 70.