The ATAC complex represses the transcriptional program of the autophagy-lysosome pathway via its E3 ubiquitin ligase activity

The Ada two A-containing (ATAC) complex, containing histone acetyltransferases general control non-derepressible 5 (GCN5) or p300/CBP-associated factor (PCAF), has gained recognition as a prominent transcriptional coactivator. Recent revelations unveiled E3 ligase activity present in both GCN5 and PCAF; however, how the dual enzymatic activities of the ATAC complex orchestrate distinct transcriptional programs and signaling networks remains largely elusive. Our study unveils the function of the ATAC complex as a negative regulator of the autophagy-lysosome pathway's transcriptional program by modulating the stability of transcription factors TFE3 and TFEB. The ATAC complex primarily impacts TFE3/TFEB destabilization through its E3 ligase activity rather than its acetyltransferase function. GCN5/PCAF-mediated ubiquitination prompts the proteasome-dependent degradation of TFE3 and TFEB. Furthermore, inactivation of the ATAC complex amplifies TFE3/TFEB-mediated autophagy-lysosome functions, thereby promoting cell survival during nutrient deprivation. In summary, our findings establish the "ATAC complex-TFE3/TFEB-autophagy-lysosome" axis as an intrinsic regulatory pathway for resisting starvation-induced cell death.