Non-canonical role of ATG4B in PRMT1-mediated DNA repair and leukemia progression

Accumulating evidence indicates that many ATG (autophagy related) proteins perform non-canonical functions beyond their canonical roles in autophagy, particularly when they localize to subcellular compartments outside the cytoplasm. Although the autophagic functions of ATG4B (autophagy related 4B, cysteine peptidase) are well established, its potential non-canonical roles, especially under metabolic stress, remain largely unexplored. In our recent study, we show that energy deprivation induces autophagy-independent nuclear translocation of ATG4B. In the nucleus, ATG4B interacts with and cleaves PRMT1 (protein arginine methyltransferase 1), thereby reducing PRMT1-mediated methylation of the DNA-repair nuclease MRE11 and consequently impairing DNA repair. Notably, ATG4B is significantly upregulated in acute myeloid leukemia (AML) and shows prominent nuclear accumulation. Genetic knockdown or pharmacological inhibition of ATG4B in AML cells restores DNA repair capacity, activates the cell-cycle checkpoint kinase CHEK1/CHK1, attenuates malignant progression, and ultimately delays leukemia progression. These findings reveal an autophagy-independent role for nuclear ATG4B that links metabolic stress to the suppression of DNA repair and identify ATG4B as a potential therapeutic target in AML.