FBXO22泛素化降解AIF的分子机制及其在肿瘤发病中的意义

凋亡诱导因子（Apoptosis-inducing factor，AIF）不仅参与细胞凋亡，而且通过稳定线粒体呼吸链复合体参与细胞代谢，为细胞存活所必须。最近，本课题组在«EMBO reports»报道AIF敲除引起PTEN氧化失活，导致肿瘤细胞发生EMT, 促进结直肠癌的转移。在此基础上，我们通过免疫沉淀技术发现F-box E3连接酶家族蛋白成员FBXO22与AIF相互结合，进一步泛素化AIF并下调其蛋白表达水平。TCGA数据库分析结果显示FBXO22在肿瘤组织中高表达，且结直肠癌病人癌组织中FBXO22高表达而AIF低表达，两者呈现显著负相关。本课题将以这些重要创新性发现为基础，深入研究FBXO22泛素化降解AIF的分子机制，探讨这种调控在肿瘤细胞代谢及肿瘤转移过程中的潜在作用。这不仅可能为AIF表达调控的机制提出新的观点及揭示FBXO22的新功能，而且渴望为肿瘤治疗提供新的线索。

Apoptosis-inducing factor (AIF) was originally identified to play a key role to execution of caspase-independent cell death. It is also believed that AIF, a protein critical for cell survival, plays an important role in the maintenance of cell metabolism, and the redox activity of AIF is essential for optimal oxidative phosphorylation. Our recent work showed that AIF protects PTEN from oxidation and inhibits epithelial–mesenchymal transition (EMT) and metastasis of colorectal cancer cells. On this basis, we found that F-box E3 ligase family protein FBXO22 can interact with AIF by immune precipitation technique, further target AIF for ubiquitylation and degradation. In addition, the TCGA database analysis showed that FBXO22 is highly expressed in tumor tissues, human colorectal cancer patients present higher FBXO22 protein level and lower AIF protein level. FBXO22 has significant negative correlation with AIF expression in human colorectal cancer patients. Based on these original findings, we aimed to further study the mechanisms of FBXO22-mediated AIF ubiquitylation and degradation, the potential roles of AIF regulated by FBXO22 in tumor cell metabolism and metastasis. The work will not only shed new insights for understanding the mechanisms of AIF expression regulation and uncovering new biological functions of FBXO22, but also provide new clues for cancer treatment.