TP53/p53-FBXO22-TFEB controls basal autophagy to govern hormesis
TP53/p53-FBXO22-TFEB controls basal autophagy to govern hormesis
复制标题
TP 53/p53-FBXO 22-TFEB控制基础自噬以控制兴奋效应
DOI：
10.1080/15548627.2021.1897961
复制
发表时间：
2021-03-13
期刊：
影响因子：
13.3
通讯作者：
Nakanishi, Makoto
中科院分区：
文献类型：
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作者：
Suzuki, Narumi;Johmura, Yoshikazu;Nakanishi, Makoto
使用轻度应激源（如禁食）进行预处理是减少后续化疗或放疗严重副作用的一种有希望的方法。然而，基本机制在很大程度上尚未探索。在这里，我们证明了TP 53/p53-FBXO 22-TFEB（转录因子EB）轴通过上调基础巨自噬/自噬在这一过程中起着至关重要的作用。轻度应激激活的TP 53转录诱导FBXO 22，FBXO 22反过来泛素化KDM 4 B（赖氨酸特异性脱甲基酶4 B）与MYC-NCOR 1抑制因子复合降解，导致TFEB的转录诱导。通过增加TFEB上调自噬相关基因显著增强了严重应激后的自噬活性和细胞存活。有丝分裂原诱导的AKT 1激活通过KDM 4 B的磷酸化来抵消这一过程，KDM 4 B抑制FBXO 22介导的泛素化。此外，fbxo 22（-/-）小鼠在出生后10小时内死亡，它们的小鼠胚胎成纤维细胞（MEFs）显示出较低的基础自噬，而FBXO 22过表达小鼠对化疗具有抗性。综上所述，这些结果表明TP 53通过FBXO 22-TFEB轴上调基础自噬，该轴控制化疗中的激素效应。
Preconditioning with a mild stressor such as fasting is a promising way to reduce severe side effects from subsequent chemo- or radiotherapy. However, the underlying mechanisms have been largely unexplored. Here, we demonstrate that the TP53/p53-FBXO22-TFEB (transcription factor EB) axis plays an essential role in this process through upregulating basal macroautophagy/autophagy. Mild stress-activated TP53 transcriptionally induced FBXO22, which in turn ubiquitinated KDM4B (lysine-specific demethylase 4B) complexed with MYC-NCOR1 suppressors for degradation, leading to transcriptional induction of TFEB. Upregulation of autophagy-related genes by increased TFEB dramatically enhanced autophagic activity and cell survival upon following a severe stressor. Mitogen-induced AKT1 activation counteracted this process through the phosphorylation of KDM4B, which inhibited FBXO22-mediated ubiquitination. Additionally, fbxo22(-/-) mice died within 10 h of birth, and their mouse embryonic fibroblasts (MEFs) showed a lowered basal autophagy, whereas FBXO22-overexpressing mice were resistant to chemotherapy. Taken together, these results suggest that TP53 upregulates basal autophagy through the FBXO22-TFEB axis, which governs the hormetic effect in chemotherapy.