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

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.

Proc Natl Acad Sci U S A

2016-09-27 / vol 113 / pages 11004-9

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.

Read on PubMed

10.1073/pnas.1602751113

1091-6490 (Electronic) 0027-8424 (Linking)

PMCID: PMC5047149

IGMM team(s) involved in this publication
Tags

E4f1; Pdh; pyruvate; skin; stem cell

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