TDP-43 associates with stalled ribosomes and contributes to cell survival during cellular stress
TDP-43 associates with stalled ribosomes and contributes to cell survival during cellular stress
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DOI：
10.1111/jnc.12194
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发表时间：
2013-07-01
影响因子：
4.7
通讯作者：
Wada, Keiji
中科院分区：
文献类型：
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作者：
Higashi, Shinji;Kabuta, Tomohiro;Wada, Keiji
TAR dna结合蛋白43 （TDP-43）是肌萎缩性侧索硬化症和额颞叶变性的重要因素。为了了解TDP-43在复杂的翻译调控机制中的生理作用，我们将培养细胞暴露在亚砷酸钠（ARS）诱导的氧化应激中不同时间，导致非致死或亚致死损伤。多体谱分析显示，ars诱导的应激导致TDP-43通过与mRNA的结合与停滞核糖体结合，而在稳态条件下没有发现这种情况。当细胞暴露于短期/非致死应激时，TDP-43与应激颗粒定位的核糖体（SGs）相关；这种联系是短暂的，因为它会随着应力的消除而立即消失。相反，当细胞暴露于长期/亚致死应激时，TDP-43被排除在SGs之外，并转移到不与mRNA结合的重组分。在这些严重应激的细胞中，TDP-43的生化改变，如不溶性增加和二硫键形成，是不可逆的。TDP-43最终通过ars诱导的c-jun n -末端激酶途径被磷酸化。在tdp -43沉默的细胞中，亚致死应激破坏了mRNA和poly (A)(+) RNA的稳定性，增加了细胞毒性。因此，TDP-43与停滞的核糖体相关，并有助于细胞应激时的细胞存活。
TAR DNA-binding protein 43 (TDP-43) has emerged as an important contributor to amyotrophic lateral sclerosis and frontotemporal lobar degeneration. To understand the physiological roles of TDP-43 in the complex translational regulation mechanisms, we exposed cultured cells to oxidative stress induced by sodium arsenite (ARS) for different periods of time, leading to non-lethal or sublethal injury. Polysome profile analysis revealed that ARS-induced stress caused the association of TDP-43 with stalled ribosomes via binding to mRNA, which was not found under the steady-state condition. When the cells were exposed to short-term/non-lethal stress, TDP-43 associating with ribosomes localized to stress granules (SGs); this association was transient because it was immediately dissolved by the removal of the stress. In contrast, when the cells were exposed to long-term/sublethal stress, TDP-43 was excluded from SGs and shifted to the heavy fractions independent of any binding to mRNA. In these severely stressed cells, biochemical alterations of TDP-43, such as increased insolubility and disulfide bond formation, were irreversible. TDP-43 was finally phosphorylated via the ARS-induced c-jun N-terminal kinase pathway. In TDP-43-silenced cells, stalled mRNA and poly (A)(+) RNA stability was disturbed and cytotoxicity increased under sublethal stress. Thus, TDP-43 associates with stalled ribosomes and contributes to cell survival during cellular stress.