Abstract
Rapidly proliferating cells reshape their metabolism to satisfy their ever-lasting need for cellular building blocks. This phenomenon is exemplified in certain malignant conditions such as cancer but also during embryonic development when cells rely heavily on glycolytic metabolism to exploit its metabolic intermediates for biosynthetic processes. How cells reshape their metabolism is not fully understood. Here we report that loss of cathepsin L (Cts L) is associated with a fast proliferation rate and enhanced glycolytic metabolism that depend on lactate dehydrogenase A (LDHA) activity. Using mass spectrometry analysis of cells treated with a pan cathepsin inhibitor, we observed an increased abundance of proteins involved in central carbon metabolism. Further inspection of putative Cts L targets revealed an enrichment for glycolytic metabolism that was independently confirmed by metabolomic and biochemical analyses. Moreover, proteomic analysis of Cts L-knockout cells identified LDHA overexpression that was demonstrated to be a key metabolic junction in these cells. Lastly, we show that Cts L inhibition led to increased LDHA protein expression, suggesting a causal relationship between LDHA expression and function. In conclusion, we propose that Cts L regulates this metabolic circuit to keep cell division under control, suggesting the therapeutic potential of targeting this protein and its networks in cancer.
Highlights
Proliferating cells reshape their metabolism to satisfy their ever-lasting need for cellular building blocks
Pharmacologic Inhibition of Lactate Dehydrogenase A Uncovers A Metabolic Determinant in Cathepsin L Knockout Cells—So far, we showed that Cts LϪ/Ϫ mouse embryonic fibroblasts (MEFs) rely heavily on glycolytic metabolism (Fig. 2), together with the fact that lactate dehydrogenase A (LDHA) is overexpressed in these cells (Fig. 4C, 4D) raising the hypothesis that LDHA drives this metabolic phenotype
We demonstrate that cathepsin L (Cts L) plays a role in cell metabolism
Summary
Remodeling of cellular metabolism is a genuine feature of rapidly growing cells. we report that mouse embryonic fibroblasts, lacking the Cathepsin L (Cts L) gene, proliferate faster than wild-types and display a noticeable glycolytic shift to satisfy their ever-growing metabolic needs. Mass spectrometry analyses identified LDHA as an essential metabolic junction in these cells, and downstream biochemical studies suggested that Cts L regulates LDHA expression and function Together, these data uncover an unprecedented role for Cathepsin L in cell metabolism. In the context of cell metabolism, a seminal study by Prudova et al, for example, recently managed to identify a novel Cts B cleavage site in the Pyruvate kinase M2, a ratelimiting enzyme in glycolysis pathway, thereby providing a mechanistic link between cathepsin activity and glycolysis in pancreatic cancer cells [10] Despite these advances, our current understanding on how Cts B or Cts L regulate metabolic processes remains limited. We found that Cts L inhibition alters LDHA turnover and increases its protein abundance, suggesting Cts L-mediated proteolysis is an essential regulatory step for adapting metabolic activity to increased metabolic needs
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