E4F1-mediated control of pyruvate dehydrogenase activity is essential for skin homeostasis.

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State: Public
Version: Final published version
Serval ID
serval:BIB_7724257A03B7
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
E4F1-mediated control of pyruvate dehydrogenase activity is essential for skin homeostasis.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Goguet-Rubio P., Seyran B., Gayte L., Bernex F., Sutter A., Delpech H., Linares L.K., Riscal R., Repond C., Rodier G., Kirsh O., Touhami J., Noel J., Vincent C., Pirot N., Pavlovic G., Herault Y., Sitbon M., Pellerin L., Sardet C., Lacroix M., Le Cam L.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
27/09/2016
Peer-reviewed
Oui
Volume
113
Number
39
Pages
11004-11009
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
The multifunctional protein E4 transcription factor 1 (E4F1) is an essential regulator of epidermal stem cell (ESC) maintenance. Here, we found that E4F1 transcriptionally regulates a metabolic program involved in pyruvate metabolism that is required to maintain skin homeostasis. E4F1 deficiency in basal keratinocytes resulted in deregulated expression of dihydrolipoamide acetyltransferase (Dlat), a gene encoding the E2 subunit of the mitochondrial pyruvate dehydrogenase (PDH) complex. Accordingly, E4f1 knock-out (KO) keratinocytes exhibited impaired PDH activity and a redirection of the glycolytic flux toward lactate production. The metabolic reprogramming of E4f1 KO keratinocytes associated with remodeling of their microenvironment and alterations of the basement membrane, led to ESC mislocalization and exhaustion of the ESC pool. ShRNA-mediated depletion of Dlat in primary keratinocytes recapitulated defects observed upon E4f1 inactivation, including increased lactate secretion, enhanced activity of extracellular matrix remodeling enzymes, and impaired clonogenic potential. Altogether, our data reveal a central role for Dlat in the metabolic program regulated by E4F1 in basal keratinocytes and illustrate the importance of PDH activity in skin homeostasis.

Keywords
Animals, Animals, Newborn, Basement Membrane/metabolism, Cell Adhesion, Cells, Cultured, Cellular Microenvironment, DNA-Binding Proteins/deficiency, DNA-Binding Proteins/metabolism, Dihydrolipoyllysine-Residue Acetyltransferase/genetics, Dihydrolipoyllysine-Residue Acetyltransferase/metabolism, Epidermis/cytology, Epidermis/metabolism, Gene Expression Regulation, Homeostasis, Keratinocytes/cytology, Keratinocytes/metabolism, Mice, Knockout, Mitochondrial Proteins/genetics, Mitochondrial Proteins/metabolism, Monocarboxylic Acid Transporters/metabolism, Muscle Proteins/metabolism, Pyruvates/metabolism, RNA, Messenger/genetics, RNA, Messenger/metabolism, Skin/metabolism, Stem Cells/metabolism, Transcription Factors/deficiency, Transcription Factors/metabolism, E4F1, PDH, pyruvate, skin, stem cell
Pubmed
Web of science
Open Access
Yes
Create date
23/09/2016 19:02
Last modification date
20/08/2019 15:34
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