The emerging role of PKM in keratinocyte homeostasis and pathophysiology

• Published in: The FEBS journal Vol. 290; no. 9; pp. 2311 - 2319
• Main Authors: Demeter, Jenna B., Elshaarrawi, Ahmed, Dowker‐Key, Presley D., Bettaieb, Ahmed
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2023
• Subjects: CRISPR; CRISPR/Cas9 system; gene editing; Gene expression; Genetic modification; Glycolysis; Glycolysis - genetics; Homeostasis; Humans; inflammation; Isoforms; Keratinocytes; Metabolism; Molecular modelling; Muscles - metabolism; Pathophysiology; Perturbation; PKM1; PKM2; proliferation; Protein Isoforms - metabolism; psoriasis; Pyruvate kinase; Pyruvate Kinase - genetics; Pyruvate Kinase - metabolism; Pyruvic acid; RNA Splicing; Skin diseases; Therapeutic applications; Therapeutic targets; proliferation; PKM2; inflammation; psoriasis; glycolysis; PKM1; keratinocytes; CRISPR/Cas9 system; gene editing
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16700

Increased aerobic glycolysis in keratinocytes has been reported as a hallmark of skin diseases while its pharmacological inhibition restores keratinocyte homeostasis. Pyruvate kinase muscle (PKM) isoforms are key enzymes in the glycolytic pathway and, therefore, an attractive therapeutic target. Simon Nold and colleagues used CRISPR/Cas9‐mediated gene editing to investigate the outcomes of PKM splicing perturbations and specific PKM1 or PKM2 deficiency in human HaCaT keratinocytes. Collectively, the study demonstrated different effects of PKM1 or PKM2 depletion on the reciprocal PKM isoform and on keratinocyte gene expression, metabolism and proliferation. Findings from this study provide novel insights into the role of PKM in keratinocyte homeostasis, warranting additional investigations into the underlying molecular mechanisms and potential therapeutic applications. Pyruvate kinase muscle (PKM) isoforms are key glycolytic pathway enzymes and, therefore, attractive therapeutic targets. Simon Nold and colleagues investigated the effect of PKM splicing perturbations and PKM1 or PKM2 deficiency on human HaCaT keratinocytes. They demonstrated different effects of PKM1 or PKM2 depletion on the reciprocal PKM isoform and on keratinocyte gene expression, metabolism and proliferation. These results highlight the role of PKM in keratinocyte homeostasis, warranting additional investigations into the underlying molecular mechanisms and potential therapeutic applications. Comment on: https://doi.org/10.1111/febs.16625