USF2 and TFEB compete in regulating lysosomal and autophagy genes

Jaebeom Kim, Young Suk Yu, Yehwa Choi, Do Hui Lee, Soobin Han, Junhee Kwon, Taichi Noda, Masahito Ikawa, Dongha Kim, Hyunkyung Kim, Andrea Ballabio, Keun Il Kim () and Sung Hee Baek ()
Additional contact information
Jaebeom Kim: School of Biological Sciences, Seoul National University
Young Suk Yu: School of Biological Sciences, Seoul National University
Yehwa Choi: School of Biological Sciences, Seoul National University
Do Hui Lee: School of Biological Sciences, Seoul National University
Soobin Han: School of Biological Sciences, Seoul National University
Junhee Kwon: Sookmyung Women’s University
Taichi Noda: Osaka University
Masahito Ikawa: Osaka University
Dongha Kim: The Catholic University of Korea
Hyunkyung Kim: Korea University College of Medicine
Andrea Ballabio: Telethon Institute of Genetics and Medicine (TIGEM)
Keun Il Kim: Sookmyung Women’s University
Sung Hee Baek: School of Biological Sciences, Seoul National University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Autophagy, a highly conserved self-digestion process crucial for cellular homeostasis, is triggered by various environmental signals, including nutrient scarcity. The regulation of lysosomal and autophagy-related processes is pivotal to maintaining cellular homeostasis and basal metabolism. The consequences of disrupting or diminishing lysosomal and autophagy systems have been investigated; however, information on the implications of hyperactivating lysosomal and autophagy genes on homeostasis is limited. Here, we present a mechanism of transcriptional repression involving upstream stimulatory factor 2 (USF2), which inhibits lysosomal and autophagy genes under nutrient-rich conditions. We find that USF2, together with HDAC1, binds to the CLEAR motif within lysosomal genes, thereby diminishing histone H3K27 acetylation, restricting chromatin accessibility, and downregulating lysosomal gene expression. Under starvation, USF2 competes with transcription factor EB (TFEB), a master transcriptional activator of lysosomal and autophagy genes, to bind to target gene promoters in a phosphorylation-dependent manner. The GSK3β-mediated phosphorylation of the USF2 S155 site governs USF2 DNA-binding activity, which is involved in lysosomal gene repression. These findings have potential applications in the treatment of protein aggregation-associated diseases, including α1-antitrypsin deficiency. Notably, USF2 repression is a promising therapeutic strategy for lysosomal and autophagy-related diseases.

Date: 2024
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DOI: 10.1038/s41467-024-52600-2

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