PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence Journal Article
| Authors: | Xiao, M.; Wu, C. H.; Meek, G.; Kelly, B.; Castillo, D. B.; Young, L. E. A.; Martire, S.; Dhungel, S.; McCauley, E.; Saha, P.; Dube, A. L.; Gentry, M. S.; Banaszynski, L. A.; Sun, R. C.; Kikani, C. K. |
| Article Title: | PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence |
| Abstract: | Quiescent stem cells are activated in response to a mechanical or chemical injury to their tissue niche. Activated cells rapidly generate a heterogeneous progenitor population that regenerates the damaged tissues. While the transcriptional cadence that generates heterogeneity is known, the metabolic pathways influencing the transcriptional machinery to establish a heterogeneous progenitor population remains unclear. Here, we describe a novel pathway downstream of mitochondrial glutamine metabolism that confers stem cell heterogeneity and establishes differentiation competence by countering post-mitotic self-renewal machinery. We discovered that mito-chondrial glutamine metabolism induces CBP/EP300-dependent acetylation of stem cell-specific kinase, PAS domain-containing kinase (PASK), resulting in its release from cytoplasmic granules and subsequent nuclear migration. In the nucleus, PASK catalytically outcompetes mitotic WDR5-anaphase-promoting complex/cyclosome (APC/C) interaction resulting in the loss of post-mitotic Pax7 expression and exit from self-renewal. In concordance with these findings, genetic or pharmacological inhibition of PASK or glutamine metabolism upregulated Pax7 expression, reduced stem cell heterogeneity, and blocked myogenesis in vitro and muscle regeneration in mice. These results explain a mechanism whereby stem cells co-opt the proliferative functions of glutamine metabolism to generate transcriptional heterogeneity and establish differentiation competence by countering the mitotic self-renewal network via nuclear PASK. © 2023, eLife Sciences Publications Ltd. All rights reserved. |
| Keywords: | signal transduction; controlled study; protein expression; protein phosphorylation; human cell; nonhuman; cell proliferation; mitosis; animal cell; mouse; animal; animals; mice; animal tissue; cell survival; cells, cultured; confocal microscopy; animal experiment; small interfering rna; tissue regeneration; genetic transcription; cell differentiation; physiology; cell heterogeneity; stem cell; genetic transfection; cell culture; chromatin immunoprecipitation; western blotting; cell isolation; stem cells; protein structure; sequence homology; ubiquitin protein ligase e3; fluorescence activated cell sorting; energy metabolism; transcription factor sox2; glutamine; nuclear reprogramming; gas chromatography; muscle regeneration; muscle development; wnt signaling; e1a associated p300 protein; cell synchronization; anaphase promoting complex; cell energy; cell granule; carboxylation; triple quadrupole mass spectrometry; human; male; article |
| Journal Title: | eLife |
| Volume: | 12 |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications Ltd. |
| Date Published: | 2023-04-13 |
| Start Page: | e81717 |
| Language: | English |
| DOI: | 10.7554/eLife.81717 |
| PUBMED: | 37052079 |
| PROVIDER: | scopus |
| PMCID: | PMC10162801 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2023 -- Source: Scopus |
