Dual pathways of TFEB activation under lysosomal stress: ATG conjugation-dependent and -independent modes

TFEB (transcription factor EB) regulates the expression of autophagy and lysosomal genes, is activated by various cellular stresses, and plays a key role in maintaining cellular homeostasis. Recent work demonstrates that TFEB is activated during lysosomal damage through two distinct mechanisms: ATG conjugation-dependent and -independent. TFEB activation proceeds sequentially through two modes. In the early ATG conjugation-independent mode (Mode I), APEX1 interacts with TFEB in the nucleus, maintaining its transcriptional activity and protein stability. In the later ATG conjugation-dependent mode (Mode II), CCT7 and TRIP6 translocate to lysosomes and interact with TFEB, modulating its phosphorylation and nuclear localization. Moreover, TFEB regulation induced by other cellular stresses-such as oxidative stress, proteasome inhibition, mitochondrial damage, and DNA damage-also involves either Mode I or Mode II. Our findings provide new insights into a unified understanding of TFEB regulation under diverse cellular stress conditions.