The ATAC complex represses the transcriptional program of the autophagy-lysosome pathway via its E3 ubiquitin ligase activity
Xiaolu Wang,
Lingling Wang,
Zhili Zhou,
Chenhao Jiang,
Ziyu Bao,
Yuexin Wang,
Ying Zhang,
Lili Song,
Yueling Zhao,
Xinying Li,
Qianqian Li,
Yujun Shen,
Ying Yu,
Wenyi Mi
Affiliations
Xiaolu Wang
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Tianjin Medical University, Tianjin 300070, China
Lingling Wang
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Zhili Zhou
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Chenhao Jiang
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Ziyu Bao
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Yuexin Wang
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Tianjin Medical University, Tianjin 300070, China
Ying Zhang
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Lili Song
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Yueling Zhao
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Xinying Li
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Qianqian Li
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Yujun Shen
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Tianjin Medical University, Tianjin 300070, China
Ying Yu
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Tianjin Medical University, Tianjin 300070, China; Corresponding author
Wenyi Mi
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Corresponding author
Summary: 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.
