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

Sungyun Cho, Yujin Chun, Long He, Cuauhtemoc B. Ramirez, Kripa S. Ganesh, Kyungjo Jeong, Junho Song, Jin Gyu Cheong, Zhongchi Li, Jungmin Choi, Joohwan Kim, Nikos Koundouros, Fangyuan Ding, Noah Dephoure, Cholsoon Jang, John Blenis, Gina Lee

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3010-3026.e8
JournalMolecular Cell
Volume83
Issue number16
DOIs
Publication statusPublished - 2023 Aug 17

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Inc.

Keywords

  • FAM120A
  • RNA splicing
  • RNA stability
  • SREBP
  • SRPK2
  • SRSF1
  • lipid metabolism
  • mTOR signaling

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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