USF2 and TFEB Compete in Regulating Lysosomal and Autophagy Genes

Authors

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
Sung Hee Baek

Publication Date

9-27-2024

Journal

Nature Communications

DOI

10.1038/s41467-024-52600-2

PMID

39333072

PMCID

PMC11436898

PubMedCentral® Posted Date

9-27-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Lysosomes, Autophagy, Humans, Upstream Stimulatory Factors, Phosphorylation, Histone Deacetylase 1, Glycogen Synthase Kinase 3 beta, Gene Expression Regulation, Promoter Regions, Genetic, HEK293 Cells, Animals, Histones, HeLa Cells, Mice, Acetylation, Autophagy, Epigenetics, Transcription, Chromatin

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.