SCFβ-TrCP ubiquitinates CHK1 in an AMPK-dependent manner in response to glucose deprivation
SCFβ-TrCP ubiquitinates CHK1 in an AMPK-dependent manner in response to glucose deprivation
复制标题
SCFbeta-TrCP 以 AMPK 依赖性方式泛素化 CHK1，以响应葡萄糖剥夺。
DOI：
10.1002/1878-0261.12403
复制
发表时间：
2019-02-01
影响因子：
6.6
通讯作者：
Zhao, Yongchao
中科院分区：
文献类型：
--
作者：
Ma, Ying;Cui, Danrui;Zhao, Yongchao
ATR/CHK1通路是细胞对DNA损伤反应的关键效应器，因此是基因组稳定性的关键调节因子。虽然ATR/CHK1途径经常因突变而失活，但CHK1本身在人类癌症中很少发生突变。因此，CHK1的细胞水平可能在维持基因组稳定性和预防肿瘤发生中发挥关键作用。由于癌细胞的高糖酵解率和血管生成不足，在许多实体肿瘤中观察到葡萄糖缺乏，但癌细胞已经设计出在低糖条件下生存的机制。虽然先前已经报道了缺糖后通过泛素-蛋白酶体途径降解CHK1，但具体的分子机制仍不清楚。在这里，我们证明了CHK1是泛素化的，并在缺糖时被Skp1-cullin-F-box(β-TrCP)E3泛素连接酶降解。具体地说，CHK1包含一个β-TrCP可识别的degron结构域，AMPK在缺糖时将其磷酸化，使β-TrCP识别CHK1，从而实现随后的泛素化和降解。我们的结果提供了一种新的机制，通过葡萄糖代谢调节DNA损伤效应，并暗示葡萄糖剥夺，通常在实体肿瘤微环境中发现，可能通过触发CHK1降解来促进突变、克隆扩张和肿瘤进展。
The ATR/CHK1 pathway is a key effector of cellular response to DNA damage and therefore is a critical regulator of genomic stability. While the ATR/CHK1 pathway is often inactivated by mutations, CHK1 itself is rarely mutated in human cancers. Thus, cellular levels of CHK1 likely play a key role in the maintenance of genomic stability and preventing tumorigenesis. Glucose deprivation is observed in many solid tumors due to high glycolytic rates of cancer cells and insufficient vascularization, yet cancer cells have devised mechanisms to survive in conditions of low glucose. Although CHK1 degradation through the ubiquitin-proteasome pathway following glucose deprivation has been previously reported, the detailed molecular mechanisms remain elusive. Here, we show that CHK1 is ubiquitinated and degraded upon glucose deprivation by the Skp1-Cullin-F-box (beta-TrCP) E3 ubiquitin ligase. Specifically, CHK1 contains a beta-TrCP recognizable degron domain, which is phosphorylated by AMPK in response to glucose deprivation, allowing for beta-TrCP to recognize CHK1 for subsequent ubiquitination and degradation. Our results provide a novel mechanism by which glucose metabolism regulates a DNA damage effector, and imply that glucose deprivation, which is often found in solid tumor microenvironments, may enhance mutagenesis, clonal expansion, and tumor progression by triggering CHK1 degradation.