Yuxiong Feng and Zhimin Lu's team: Licensing but not fueling: A metabolic enzyme promotes mitosis beyond metabolism
Uncontrolled cell proliferation is a hallmark of cancer. To sustain the ceaseless cell division, cancer cells rewire metabolic pathways in order to provide sufficient nutrient and energy for mitotic progression. Metabolic reprogramming of cancer cells is usually orchestrated by dysregulation of metabolic enzymes. It is generally thought that dysregulated metabolic enzymes contribute to cell cycle progression mainly by providing essential metabolites to meet the cellular needs for biosynthesis and bioenergenesis. However, it has been increasingly appreciated that metabolic enzymes can also conduct noncanonical or nonmetabolic functions that are referred to as “moonlighting” functions during certain physiological and pathological processes. Nonetheless, it is unclear if metabolic enzymes can directly control mitosis via metabolism-independent mechanisms.
In the latest issue of Nature Metabolism, the research groups of Yuxiong Feng and Zhimin Lu at the Institute of Translational Medicine, Zhejiang University, teamed with the group of Tingbo Liang at the First Affiliated Hospital of Medical School, Zhejiang University, published a research article entitled “Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth”. They identified an enzyme-independent function of glutamine synthetase (GS) in promoting mitosis by activating the APC/Ccdc20 complex. These findings provide new insights into the role of glutamine metabolism in cancer cell proliferation.
GS is the only enzyme in mammals to produce glutamine from glutamate. In this report, the authors reported that in response to adequate glutamine supply GS reduces its catalytic activity and promotes cell proliferation by licensing mitotic progression independent of its metabolic function. GS depletion, but not impairment of its enzymatic activity, results in mitotic arrest and multinucleation across multiple cancer cell lines, patient-derived organoids, and xenografted tumors. Mechanistically, GS directly interacts with the nuclear pore protein NUP88 to prevent its binding to CDC20. Such interaction licenses activation of CDC20-mediated APC/C to ensure proper metaphase-to-anaphase transition. In addition, GS is overexpressed in human non-small cell lung cancer, and its depletion reduces tumor growth in mice and increases the efficacy of microtubule-targeted chemotherapy. Overall, these findings highlight a novel moonlighting function of GS in governing mitosis and illustrate how an essential metabolic enzyme promotes cell proliferation and tumor development, beyond its main metabolic function.
This study was supported by the grants of the National Natural Science Foundation of China, the Ministry of Science and Technology of the People's Republic of China, and the Zhejiang Provincial Natural Science Foundation of China.