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

doi:10.1016/j.molcel.2023.07.017

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.

Authors

Sungyun Cho¹, Yujin Chun², Long He¹, Cuauhtemoc B Ramirez³, Kripa S Ganesh⁴, Kyungjo Jeong⁵, Junho Song⁵, Jin Gyu Cheong⁶, Zhongchi Li¹, Jungmin Choi⁷, Joohwan Kim², Nikos Koundouros⁸, Fangyuan Ding⁹, Noah Dephoure¹⁰, Cholsoon Jang¹¹, John Blenis¹², Gina Lee¹³

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: job2064@med.cornell.edu.
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: ginalee@uci.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Arginine*
Humans
Lipogenesis* / genetics
Mechanistic Target of Rapamycin Complex 1 / genetics
RNA Splicing Factors
Sterol Regulatory Element Binding Protein 1* / metabolism
Sterol Regulatory Element Binding Proteins / metabolism

Substances

Arginine
Mechanistic Target of Rapamycin Complex 1
RNA Splicing Factors
Sterol Regulatory Element Binding Protein 1
FAM120A protein, human
Sterol Regulatory Element Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding