FBXO22-mediated Ubiquitination And Degradation Of AIF And Its Role In Cancer Cell Apoptosis

F-box only protein 22（FBXO22）is a member of the F-box protein family responsible for the specific recruitment and binding of substrates in the ubiquitin ligase complex SCF,and its biological functions are rarely studied.Recently,our research group has been devoted to identifying the substrates of FBXO22 and discovering new functions.First,we found that FBXO22 binds to serine/threonine protein kinase LKB1,and FBXO22inhibits activity of LKB1 to promote the growth of lung cancer cells through polyubiquitination.Second,we also showed that FBXO22 ubiquitinates and degrades nuclear PTEN to promote tumorigenesis.In this study,FBXO22 wasfound to interact with AIF by immunoprecipitation with mass spectrometry,and we confirmed that FBXO22mediated AIF ubiquitination modification and inhibited its protein expression.TCGA database analysis showed that FBXO22 is highly expressed in most tumors including colorectal cancer.AIF can be released into the nucleus from mitochondria under the stimulation of alkalization agent damage and oxidative stress,and induce programmed cell apoptosis.On this basis,we used sh RNA to knock down FBXO22 in colon cancer cell lines,and found that inhibition of FBXO22 could stabilize the expression of AIF in the nucleus and promote the apoptosis of colon cancer cells induced by MNNG and H₂O_2.Conversely,overexpression of FBXO22 inhibits drug-induced apoptosis in colon cancer cells.In summary,these original results showed that FBXO22 is the first reported E3ligase that degrades AIF protein and regulates the apoptosis of cancer cells through AIF.This not only reveals the new function of FBXO22,but also is expected to provide new potential targets for the precise treatment of tumors.