机械代谢靶标拉帕霉素复合物1（mTORC1）是细胞生长的主要调节因子，通过转录、RNA加工和代谢酶的翻译后修饰来促进大分子合成。然而，mTORC1如何协调基因表达程序的多个步骤仍不清楚。在此，我们发现序列相似性家族120A（FAM120A）是一个转录共激活因子，它连接了mTORC1-丝氨酸/精氨酸富集蛋白激酶2（SRPK2）信号传导下的脂类合成酶的转录和剪接。mTORC1激活的SRPK2磷酸化剪接因子丝氨酸/精氨酸富集剪接因子1（SRSF1），增强其与FAM120A的结合。FAM120A直接与一个脂类合成转录因子SREBP1在活性启动子处相互作用，从而将新转录的脂类合成基因从RNA聚合酶II桥接到含有SRSF1和U1-70K的RNA剪接机制中。这种mTORC1调控的多蛋白复合物促进了脂类合成转录本的高效剪接和稳定，从而导致脂肪酸合成和癌细胞增殖。这些结果阐明了FAM120A作为一个关键的转录共因子，连接了mTORC1依赖的基因调控程序与合成型细胞生长。© 2023 Elsevier Inc. All rights reserved.

The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that stimulates macromolecule synthesis through transcription, RNA processing, and post-translational modification of metabolic enzymes. However, the mechanisms of how mTORC1 orchestrates multiple steps of gene expression programs remain unclear. Here, we identify family with sequence similarity 120A (FAM120A) as a transcription co-activator that couples transcription and splicing of de novo lipid synthesis enzymes downstream of mTORC1-serine/arginine-rich protein kinase 2 (SRPK2) signaling. The mTORC1-activated SRPK2 phosphorylates splicing factor serine/arginine-rich splicing factor 1 (SRSF1), enhancing its binding to FAM120A. FAM120A directly interacts with a lipogenic transcription factor SREBP1 at active promoters, thereby bridging the newly transcribed lipogenic genes from RNA polymerase II to the SRSF1 and 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.Copyright © 2023 Elsevier Inc. All rights reserved.