From the Departments of Cancer Genetics and Epigenetics and.
Molecular and Cellular Endocrinology, Beckman Research Institute, City of Hope Cancer Center, Duarte, California 91010.
J Biol Chem. 2018 Sep 28;293(39):15290-15303. doi: 10.1074/jbc.RA118.004512. Epub 2018 Aug 21.
Glucose is a critical nutrient for cell proliferation. However, the molecular pathways that regulate glucose metabolism are still elusive. We discovered that co-activator-associated arginine methyltransferase 1 (CARM1) suppresses glucose metabolism toward serine biosynthesis. By tracing the C-labeled glucose, we found that knockout mouse embryonic fibroblasts exhibit significantly increased serine synthesis than WT cells. This is caused, at least in part, by the reduced pyruvate kinase (PK) activity in these cells. The M2 isoform of PK (PKM2) is arginine-methylated by CARM1, and methylation enhances its activity. Mechanistically, CARM1 methylates PKM2 at arginines 445 and 447, which enhances PKM2 tetramer formation. Consequently, knockout cells exhibit significant survival advantages over WT cells when extracellular serine is limited, likely due to their enhanced serine synthesis capacity. Altogether, we identified CARM1 as an important regulator of glucose metabolism and serine synthesis.
葡萄糖是细胞增殖的关键营养物质。然而，调节葡萄糖代谢的分子途径仍然难以捉摸。我们发现共激活因子相关精氨酸甲基转移酶 1（CARM1）抑制葡萄糖代谢向丝氨酸生物合成。通过追踪 C 标记的葡萄糖，我们发现 基因敲除的小鼠胚胎成纤维细胞表现出比 WT 细胞显著增加的丝氨酸合成。这至少部分是由于这些细胞中丙酮酸激酶（PK）活性降低所致。PK 的 M2 同工型（PKM2）被 CARM1 精氨酸甲基化，甲基化增强其活性。在机制上，CARM1 在精氨酸 445 和 447 处甲基化 PKM2，增强 PKM2 四聚体形成。因此，当细胞外丝氨酸受到限制时，基因敲除细胞比 WT 细胞表现出显著的生存优势，这可能是由于它们增强的丝氨酸合成能力。总的来说，我们确定 CARM1 是葡萄糖代谢和丝氨酸合成的重要调节因子。
