2. Academic Validation
  3. FAM120A couples SREBP-dependent transcription and splicing of lipogenesis enzymes downstream of mTORC1

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

  • Mol Cell. 2023 Aug 17;83(16):3010-3026.e8. doi: 10.1016/j.molcel.2023.07.017.
Sungyun Cho 1,  Yujin Chun 2,  Long He 1,  Cuauhtemoc B Ramirez 3,  Kripa S Ganesh 4,  Kyungjo Jeong 5,  Junho Song 5,  Jin Gyu Cheong 6,  Zhongchi Li 1,  Jungmin Choi 7,  Joohwan Kim 2,  Nikos Koundouros 8,  Fangyuan Ding 9,  Noah Dephoure 10,  Cholsoon Jang 11,  John Blenis 12,  Gina Lee 13
Affiliations

Affiliations

  • 1 Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • 2 Department of Microbiology and Molecular Genetics, School of Medicine, University of California Irvine, Irvine, CA, USA.
  • 3 Department of Microbiology and Molecular Genetics, School of Medicine, University of California Irvine, Irvine, CA, USA; Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA.
  • 4 Department of Biochemistry, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • 5 Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, South Korea.
  • 6 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • 7 Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, South Korea; Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA.
  • 8 Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • 9 Department of Biomedical Engineering, Department of Developmental and Cell Biology, Department of Pharmaceutical Sciences, Center for Synthetic Biology, and Center for Neural Circuit Mapping, University of California Irvine, Irvine, CA, USA; Center for Complex Biological Systems and Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA.
  • 10 Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • 11 Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA; Center for Complex Biological Systems and Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA; Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA.
  • 12 Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA. Electronic address: [email protected].
  • 13 Department of Microbiology and Molecular Genetics, School of Medicine, University of California Irvine, Irvine, CA, USA; Center for Complex Biological Systems and Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA; Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA. Electronic address: [email protected].
PMID: 37595559 DOI: 10.1016/j.molcel.2023.07.017
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.

Keywords

FAM120A; RNA splicing; RNA stability; SREBP; SRPK2; SRSF1; lipid metabolism; mTOR signaling.

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