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USF2 and TFEB compete in regulating lysosomal and autophagy genes.
- Source :
-
Nature communications [Nat Commun] 2024 Sep 27; Vol. 15 (1), pp. 8334. Date of Electronic Publication: 2024 Sep 27. - Publication Year :
- 2024
-
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.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Phosphorylation
Histone Deacetylase 1 metabolism
Histone Deacetylase 1 genetics
Glycogen Synthase Kinase 3 beta metabolism
Glycogen Synthase Kinase 3 beta genetics
Gene Expression Regulation
Promoter Regions, Genetic
HEK293 Cells
Animals
Histones metabolism
HeLa Cells
Mice
Acetylation
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics
Lysosomes metabolism
Autophagy genetics
Upstream Stimulatory Factors metabolism
Upstream Stimulatory Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 39333072
- Full Text :
- https://doi.org/10.1038/s41467-024-52600-2