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Peer-reviewedCC BY 4.0The Journal of Biological Chemistry

Crosstalk between NUAK1 and the SETD1A complex regulates glycolysis and gluconeogenesis upon glucose deprivation

  • Zhen Wang1
  • Yan Hao2
  • Shiyuan Chen3
  • Laurence Florens2
  • Jerry L. Workman1
  • Tamaki Suganuma1
  1. 1Workman Lab, Stowers Institute for Medical Research, Kansas City, Missouri, USA
  2. 2Systems Mass Spectrometry, Stowers Institute for Medical Research, Kansas City, Missouri, USA
  3. 3Computational Biology, Stowers Institute for Medical Research, Kansas City, Missouri, USA
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Abstract

Glucose is a crucial energy source, and glucose metabolism represents central chemical reactions in redox homeostasis. We previously found that histone H3 threonine 11 phosphorylation, which requires histone H3 lysine 4 trimethylation, promotes the transcription of genes regulating mitochondrial respiratory pathways during limited glucose in yeast. Here, we discovered that global levels of histone H3 threonine 11 phosphorylation increase during glucose depletion in human cells. The human NUAK1 kinase phosphorylates H3T11 and promotes expression of the genes regulating the p53-dependent DNA damage response upon glucose depletion. Remarkably, NUAK1 associates with the SETD1A histone H3K4 methyltransferase complex. Upon glucose depletion NUAK1 and the SETD1A complex promote expression of HK2 and PCK2, which catalyze the first rate-limiting steps of glycolysis and gluconeogenesis, respectively, in addition to genes regulating the mitochondrial respiratory pathway. In combination with constant histone H3 lysine 4 trimethylation levels during glucose depletion, NUAK1-mediated H3T11 phosphorylation may function as the anchor in the rewiring of gene expression during glucose depletion.

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Cite

BibTeXRIS
BibTeX
@article{wang2026crosstalk,
  title = {{Crosstalk between NUAK1 and the SETD1A complex regulates glycolysis and gluconeogenesis upon glucose deprivation}},
  author = {Zhen Wang and Yan Hao and Shiyuan Chen and Laurence Florens and Jerry L. Workman and Tamaki Suganuma},
  journal = {The Journal of Biological Chemistry},
  year = {2026},
  month = sep,
  doi = {10.1016/j.jbc.2026.113598},
  url = {https://doi.org/10.1016/j.jbc.2026.113598},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Crosstalk between NUAK1 and the SETD1A complex regulates glycolysis and gluconeogenesis upon glucose deprivation
AU  - Zhen Wang
AU  - Yan Hao
AU  - Shiyuan Chen
AU  - Laurence Florens
AU  - Jerry L. Workman
AU  - Tamaki Suganuma
PY  - 2026
DA  - 2026/09/23
JO  - The Journal of Biological Chemistry
DO  - 10.1016/j.jbc.2026.113598
UR  - https://doi.org/10.1016/j.jbc.2026.113598
AB  - Glucose is a crucial energy source, and glucose metabolism represents central chemical reactions in redox homeostasis. We previously found that histone H3 threonine 11 phosphorylation, which requires histone H3 lysine 4 trimethylation, promotes the transcription of genes regulating mitochondrial respiratory pathways during limited glucose in yeast. Here, we discovered that global levels of histone H3 threonine 11 phosphorylation increase during glucose depletion in human cells. The human NUAK1 kinase phosphorylates H3T11 and promotes expression of the genes regulating the p53-dependent DNA damage response upon glucose depletion. Remarkably, NUAK1 associates with the SETD1A histone H3K4 methyltransferase complex. Upon glucose depletion NUAK1 and the SETD1A complex promote expression of HK2 and PCK2, which catalyze the first rate-limiting steps of glycolysis and gluconeogenesis, respectively, in addition to genes regulating the mitochondrial respiratory pathway. In combination with constant histone H3 lysine 4 trimethylation levels during glucose depletion, NUAK1-mediated H3T11 phosphorylation may function as the anchor in the rewiring of gene expression during glucose depletion.
SN  - 0021-9258
SN  - 1083-351X
ER  -