Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity

The Carbohydrate Response Element Binding Protein (ChREBP) is a glucose-responsive transcription factor (TF) with two major splice isoforms (α and β). In chronic hyperglycemia and glucolipotoxicity, ChREBPα-mediated ChREBPβ expression surges, leading to insulin-secreting β-cell dedifferentiation and...

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Vydané v:Nature communications Ročník 16; číslo 1; s. 2110 - 16
Hlavní autori: Katz, Liora S., Visser, Emira J., Plitzko, Kathrin F., Pennings, Marloes A. M., Cossar, Peter J., Tse, Isabelle L., Kaiser, Markus, Brunsveld, Luc, Ottmann, Christian, Scott, Donald K.
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: London Nature Publishing Group UK 02.03.2025
Nature Publishing Group
Nature Portfolio
Predmet:
13/1
13/106
13/2
14-3-3 protein
14-3-3 Proteins - genetics
14-3-3 Proteins - metabolism
14/1
14/34
14/35
14/63
38/77
42/35
42/44
45/77
45/88
45/90
631/45/612/822
631/92/613
Adhesives
Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - chemistry
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism
Beta cells
Carbohydrates
Cell death
Cytoplasm
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - metabolism
Glucose - metabolism
Glucose - toxicity
Glues
Humanities and Social Sciences
Humans
Hyperglycemia
Insulin-Secreting Cells - drug effects
Insulin-Secreting Cells - metabolism
Isoforms
Mice
multidisciplinary
Protein Binding
Protein interaction
Proteins
Science
Science (multidisciplinary)
Transcription factors
ISSN:2041-1723, 2041-1723
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Shrnutí:The Carbohydrate Response Element Binding Protein (ChREBP) is a glucose-responsive transcription factor (TF) with two major splice isoforms (α and β). In chronic hyperglycemia and glucolipotoxicity, ChREBPα-mediated ChREBPβ expression surges, leading to insulin-secreting β-cell dedifferentiation and death. 14-3-3 binding to ChREBPα results in cytoplasmic retention and suppression of transcriptional activity. Thus, small molecule-mediated stabilization of this protein-protein interaction (PPI) may be of therapeutic value. Here, we show that structure-based optimizations of a ‘molecular glue’ compound led to potent ChREBPα/14-3-3 PPI stabilizers with cellular activity. In primary human β-cells, the most active compound retained ChREBPα in the cytoplasm, and efficiently protected β-cells from glucolipotoxicity while maintaining β-cell identity. This study may thus not only provide the basis for the development of a unique class of compounds for the treatment of Type 2 Diabetes but also showcases an alternative ‘molecular glue’ approach for achieving small molecule control of notoriously difficult to target TFs. Targeting transcription factors with small molecules remains a significant challenge in drug discovery. Here, the authors present a structure-based approach to stabilize ChREBPα/14-3-3 interactions, suppressing ChREBPβ and protecting β-cells from glucolipotoxicity, showcasing ‘molecular glues’ as tools to control difficult to target transcription factors.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-025-57241-7