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

Published: 3 August 2023| Version 1 | DOI: 10.17632/rgfgx9xb8w.1


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.



Weill Cornell Medicine Department of Pharmacology


Cell Biology