Cells can sense the stiffness of the extracellular matrix (ECM) and use this information to regulate the cytoskeleton and modulate signalling. In a study published in Nature, Park et al. find a direct link between mechanical sensing, the cytoskeleton and metabolic regulation through the activity of the ubiquitin ligase TRIM21.
The authors found that human bronchial epithelial cells (HBECs) spread out less on soft ECM than on stiff ECM and had a lower level of glycolytic activity owing to a reduction in the level of isoforms of the glycolytic enzyme phosphofructokinase (PFK). However, non-small-cell lung carcinoma (NSCLC) cells, as well as HBECs transformed with oncogenes, were able to maintain a high glycolytic rate on soft ECM.
Overexpression of PFK only partially rescued the downregulation of glycolysis on soft ECM, suggesting post-translational regulation of PFK in this pathway. Proteasome inhibition or disruption of PFK ubiquitination increased PFK levels and rescued glycolytic activity in cells on soft substrate. Knockdown of the PFK-targeting ubiquitin ligase TRIM21 increased PFK levels, and overexpression was sufficient to reduce PFK levels in HBECs cultured on stiff ECM and in cancer cells.
The reduced rates of glycolysis in HBECs grown on soft ECM were linked to actin cytoskeleton architecture and specifically to reduced actin bundling. Indeed, HBECs expressing a mutant α-actinin 1 to induce actin bundling maintained PFK expression and glycolysis even on soft substrates. Moreover, interference with myosin or actin polymerization was sufficient to inhibit glycolysis and reduce PFK expression in HBECs, but not cancer cells, on stiff ECM.
The authors further showed that TRIM21 co-localized with stress fibres — contractile actin bundles associated with cell spreading. Induction of stress fibres reduced cytosolic TRIM21 levels, suggesting that stress fibres sequester TRIM21.
“TRIM21 is sequestered by stress fibres, which … upregulates glycolysis in response to stiff ECM”
Collectively, these results indicate that TRIM21 is sequestered by stress fibres, which prevents PFK ubiquitination and upregulates glycolysis in response to stiff ECM. These data also suggest that cancer cells can sustain high glycolytic rates through maintaining stress fibres that are insensitive to substrate stiffness.
Park, J. S. et al. Mechanical regulation of glycolysis via cytoskeleton architecture. Nature https://doi.org/10.1038/s41586-020-1998-1 (2020)
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Willson, J. Stress fibres fuel glycolysis. Nat Rev Mol Cell Biol 21, 180 (2020). https://doi.org/10.1038/s41580-020-0224-1