The gluconeogenesis enzyme PCK2 has a non-enzymatic role in proteostasis in endothelial cells.

Endothelial cells (ECs) are highly glycolytic, but whether they generate glycolytic intermediates via gluconeogenesis (GNG) in glucose-deprived conditions remains unknown. Here, we report that glucose-deprived ECs upregulate the GNG enzyme PCK2 and rely on a PCK2-dependent truncated GNG, whereby lactate and glutamine are used for the synthesis of lower glycolytic intermediates that enter the serine and glycerophospholipid biosynthesis pathways, which can play key roles in redox homeostasis and phospholipid synthesis, respectively. Unexpectedly, however, even in normal glucose conditions, and independent of its enzymatic activity, PCK2 silencing perturbs proteostasis, beyond its traditional GNG role. Indeed, PCK2-silenced ECs have an impaired unfolded protein response, leading to accumulation of misfolded proteins, which due to defective proteasomes and impaired autophagy, results in the accumulation of protein aggregates in lysosomes and EC demise. Ultimately, loss of PCK2 in ECs impaired vessel sprouting. This study identifies a role for PCK2 in proteostasis beyond GNG.

Molecular and metabolic orchestration of the lymphatic vasculature in physiology and pathology.

Lymphangiogenesis refers to the generation of new lymphatic vessels from pre-existing ones. During development and particular adult states, lymphatic endothelial cells (LEC) undergo reprogramming of their transcriptomic and signaling networks to support the high demands imposed by cell proliferation and migration. Although there has been substantial progress in identifying growth factors and signaling pathways controlling lymphangiogenesis in the last decades, insights into the role of metabolism in lymphatic cell functions are just emerging. Despite numerous similarities between the main metabolic pathways existing in LECs, blood ECs (BEC) and other cell types, accumulating evidence has revealed that LECs acquire a unique metabolic signature during lymphangiogenesis, and their metabolic engine is intertwined with molecular regulatory networks, resulting in a tightly regulated and interconnected process. Considering the implication of lymphatic dysfunction in cancer and lymphedema, alongside other pathologies, recent findings hold promising opportunities to develop novel therapeutic approaches. In this review, we provide an overview of the status of knowledge in the molecular and metabolic network regulating the lymphatic vasculature in health and disease.