FAM120A couples SREBP-dependent transcription and splicing of lipogenesis enzymes downstream of mTORC1

The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that stimulates macromolecule synthesis upon nutrient, insulin, growth factors, and oncogenic signals. mTORC1 activates anabolic pathways by inducing posttranslational modifications of metabolic enzymes and by regulating their expression through transcription and mRNA processing. However, the mechanisms of how mTORC1 orchestrates these tightly connected processes remain unclear. Here, we identify FAM120A as a transcriptional co-activator that couples transcription and splicing of de novo lipid synthesis enzymes downstream of mTORC1-SRPK2 signaling. The mTORC1-activated SRPK2 phosphorylates a splicing factor SRSF1, enhancing its binding to FAM120A. Mechanistically, FAM120A directly interacts with a lipogenic transcription factor SREBP1 at active promoters, thereby bridging the newly transcribed lipogenic genes from RNA polymerase II to SRSF1 and the U1-70K-containing RNA splicing machinery. This mTORC1-regulated, multi-protein complex promotes efficient splicing and stability of lipogenic transcripts, resulting in fatty acid synthesis and cancer cell proliferation. These results elucidate FAM120A as a critical transcription co-factor that connects mTORC1-dependent gene regulation programs for anabolic cell growth.

雷帕霉素机制性靶标复合物1（mechanistic target of rapamycin complex 1，mTORC1）是细胞生长的核心调控因子，可响应营养物质、胰岛素、生长因子及致癌信号，进而促进大分子合成。mTORC1可通过诱导代谢酶的翻译后修饰，以及经由转录与mRNA加工调控其表达，从而激活合成代谢通路。然而，mTORC1如何协调这些紧密关联的生物学过程，其具体机制仍未明确。本研究鉴定出FAM120A是一类转录共激活因子，可在mTORC1-SRPK2信号通路下游偶联从头脂质合成酶的转录与剪接过程。经mTORC1激活的SRPK2可对剪接因子SRSF1进行磷酸化修饰，增强其与FAM120A的结合能力。机制层面上，FAM120A可在活性启动子区域与生脂转录因子SREBP1直接相互作用，从而将RNA聚合酶Ⅱ新转录的生脂基因桥接至SRSF1及含U1-70K的RNA剪接复合体。这种受mTORC1调控的多蛋白复合物可促进生脂转录本的高效剪接与稳定性，最终推动脂肪酸合成与癌细胞增殖。本研究结果阐明FAM120A是一类关键的转录共因子，可连接依赖mTORC1的合成代谢细胞生长基因调控程序。