SETD5‐Coordinated LC3B Methylation Inhibits Autophagy in Ovarian Cancer

MAP1LC3/LC3 is an essential autophagy regulator involved in both the formation of autophagosome and the recruitment of autophagy cargo. Although several post-translational modifications (PTMs) have been identified to regulate the function of LC3, the effect of protein methylation on its function has not been well characterized. Here, we show that SETD5 interacts with and methylates nuclear LC3B (a member of the LC3 subfamily) at lysines 5 and 65, leading to its nuclear retention. In the nucleus of human ovarian cancer (OC) cells, methylated LC3B binds the nuclear transcription factor PRDM10 to the promoter regions of autophagy-related genes (ATGs), including ATG2a, ATG7, ATG12, and ATG16L1, to suppress their transcription, thereby resulting in reduced formation of autophagosomes. Moreover, the methylation of LC3B facilitates OC cell migration by inhibiting autophagy. Overall, our study defines a novel modification of LC3B and unveils a SETD5-mediated methylation-dependent regulatory mechanism controlling nuclear LC3B function in autophagy and migration in OC cells, offering potential therapeutic targets for OC.