Hypoxia-induced degradation of FTO promotes apoptosis by unmasking RACK1-mediated activation of MTK1-JNK1/2 pathway

作者：Chengyu Li, Zhaojun Liu, Chen Fu, Hongmin Li, Tong He, Gang Wu, Yanan Sheng, Ming Shen, Honglin Liu · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.01.019 · 被引用次数：9 · 研究领域：RNA modifications and cancer、interferon and immune responses、Metalloenzymes and iron-sulfur proteins

A schematic model illustrating the cytoprotective role of FTO in response to type 1 stress (hypoxia) by hijacking RACK1 in the cytoplasm. Under normoxic conditions, FTO is predominantly localized within the nucleus, with a smaller fraction present in the cytoplasm. Cytoplasmic FTO binds to RACK1, impairing the interaction between RACK1 and MTK1, which diminishes JNK1/2 phosphorylation and ultimately inhibits apoptosis. Upon exposure to hypoxic stress, FTO undergoes ubiquitination by the E1 ubiquitin-activating enzyme ATG7 and the E3 ubiquitin ligase NEDD4, with both K48- and K63-linked polyubiquitination leading to FTO degradation through the ubiquitin–proteasome system (UPS) and the autophagy-lysosome pathway (ALP). To compensate for the reduced cytoplasmic FTO levels due to hypoxia-induced degradation, nuclear FTO translocates to the cytoplasm, reinforcing its anti-apoptotic function. However, these translocated FTO molecules are also susceptible to degradation. Consequently, the overall decrease in FTO levels eliminates FTO’s hijacking of RACK1, thus promoting MTK1 and RACK1 binding, which in turn activates JNK1/2 and ultimately induces apoptosis. • Hypoxia triggers the cytoplasmic translocation of FTO. • ATG7 and NEDD4 induce cytoplasmic FTO degradation through the UPS and ALP pathways. • Inhibition of FTO degradation suppresses hypoxia-induced apoptosis. • FTO competes with MTK1 for binding to the scaffolding protein RACK1. • FTO inhibits apoptosis by unmasking RACK1-med...