ZSCAN4 is negatively regulated by the ubiquitin-proteasome system and the E3 ubiquitin ligase RNF20.
ZSCAN4 is negatively regulated by the ubiquitin-proteasome system and the E3 ubiquitin ligase RNF20.
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DOI：
10.1016/j.bbrc.2018.02.155
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发表时间：
2018-03-25
影响因子：
3.1
通讯作者：
Zalzman M
中科院分区：
文献类型：
--
作者：
Portney BA;Khatri R;Meltzer WA;Mariano JM;Zalzman M
Zscan4 是在小鼠胚胎干细胞和诱导多能干细胞中表达的早期胚胎基因簇，在基因组稳定性、端粒维持和多能性中发挥着关键作用。 Zscan4 表达是瞬时的，其特点是不常见的高表达峰，但很快就会下调，表明其表达受到严格控制。然而，人们对调节人类 ZSCAN4 蛋白水平的蛋白降解途径知之甚少。在这项研究中，我们首次确定了ZSCAN4蛋白的半衰期和降解途径，包括参与该过程的关键因素，负责调节ZSCAN4的稳定性。我们证明了赖氨酸 48 特异性多泛素化和随后 ZSCAN4 的蛋白酶体依赖性降解，这可能解释了如何有效地从细胞中清除这一关键因子。重要的是，我们的数据表明 ZSCAN4 和 E3 泛素连接酶 RNF20 之间存在相互作用。此外，我们的结果表明，通过基因敲低来消除 RNF20 不会影响 ZSCAN4 转录水平，而是导致 ZSCAN4 蛋白水平增加。此外，RNF20 消耗稳定了 ZSCAN4 蛋白半衰期，表明 RNF20 负向调节 ZSCAN4 稳定性。由于 ZSCAN4 具有重要的细胞功能，我们的结果对端粒调控、干细胞生物学和癌症具有重要意义。
Zscan4 is an early embryonic gene cluster expressed in mouse embryonic stem and induced pluripotent stem cells where it plays critical roles in genomic stability, telomere maintenance, and pluripotency. Zscan4 expression is transient, and characterized by infrequent high expression peaks that are quickly down-regulated, suggesting its expression is tightly controlled. However, little is known about the protein degradation pathway responsible for regulating the human ZSCAN4 protein levels. In this study we determine for the first time the ZSCAN4 protein half-life and degradation pathway, including key factors involved in the process, responsible for the regulation of ZSCAN4 stability. We demonstrate lysine 48 specific polyubiquitination and subsequent proteasome dependent degradation of ZSCAN4, which may explain how this key factor is efficiently cleared from the cells. Importantly, our data indicate an interaction between ZSCAN4 and the E3 ubiquitin ligase RNF20. Moreover, our results show that RNF20 depletion by gene knockdown does not affect ZSCAN4 transcription levels, but instead results in increased ZSCAN4 protein levels. Further, RNF20 depletion stabilizes the ZSCAN4 protein half-life, suggesting that RNF20 negatively regulates ZSCAN4 stability. Due to the significant cellular functions of ZSCAN4, our results have important implications in telomere regulation, stem cell biology, and cancer.
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影响因子：
10.5
作者：
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