CHK2-FOXK axis promotes transcriptional control of autophagy programs
CHK2-FOXK axis promotes transcriptional control of autophagy programs
复制标题
CHK2-FOXK轴促进自噬程序的转录控制
DOI：
10.1126/sciadv.aax5819
复制
发表时间：
2020-01-01
期刊：
影响因子：
13.6
通讯作者：
Yuan, Jian
中科院分区：
文献类型：
--
作者：
Chen, Yuping;Wu, Jinhuan;Yuan, Jian
我们阐明了DNA损伤通过CHK 2-FOXK轴触发自噬，并且该途径的失调导致化学抗性。自噬是一种进化上保守的分解代谢过程，在清除错误折叠的蛋白质和清除受损细胞器以维持内环境稳态方面起着重要作用。在这里，我们发现了检查点激酶2（CHK 2）-FOXK（FOXK 1和FOXK 2）轴在转录调控层的DNA损伤介导的自噬中发挥重要作用。从机制上讲，DNA损伤后，CHK 2磷酸化FOXK并产生14-3-3γ结合位点，进而将FOXK蛋白捕获在细胞质中。由于FOXK作为ATG的转录抑制因子发挥作用，DNA损伤介导的FOXK的细胞质捕获诱导自噬。此外，我们发现癌症来源的FOXK突变诱导FOXK过度磷酸化并增强自噬，导致化疗耐药性。顺铂和氯喹联合治疗可克服FOXK突变引起的耐药。总的来说，我们的研究强调了一种机制，即DNA损伤通过CHK 2-FOXK介导的转录控制增加自噬基因来触发自噬，并且该途径的失调有助于化疗耐药性。
We clarify that DNA damage triggers autophagy by CHK2-FOXK axis, and misregulation of this pathway leads to chemoresistance. Autophagy is an evolutionarily conserved catabolic process, which plays a vital role in removing misfolded proteins and clearing damaged organelles to maintain internal environment homeostasis. Here, we uncovered the checkpoint kinase 2 (CHK2)–FOXK (FOXK1 and FOXK2) axis playing an important role in DNA damage–mediated autophagy at the transcriptional regulation layer. Mechanistically, following DNA damage, CHK2 phosphorylates FOXK and creates a 14-3-3γ binding site, which, in turn, traps FOXK proteins in the cytoplasm. Because FOXK functions as the transcription suppressor of ATGs, DNA damage–mediated FOXKs’ cytoplasmic trapping induces autophagy. In addition, we found that a cancer-derived FOXK mutation induces FOXK hyperphosphorylation and enhances autophagy, resulting in chemoresistance. Cotreatment with cisplatin and chloroquine overcomes the chemoresistance caused by FOXK mutation. Overall, our study highlights a mechanism whereby DNA damage triggers autophagy by increasing autophagy genes via CHK2-FOXK–mediated transcriptional control, and misregulation of this pathway contributes to chemoresistance.