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AMP-activated protein kinase regulates alternative pre-mRNA splicing by phosphorylation of SRSF1

Eri Matsumoto1, Kaho Akiyama1, Takuya Saito1

  • 1Department of Agricultural Chemistry, Faculty of Applied Biosciences, Tokyo University of Agriculture, Tokyo, Japan.

The Biochemical Journal
|May 27, 2020
PubMed

Insights

AMP-activated protein kinase (AMPK) directly phosphorylates serine/arginine-rich splicing factor 1 (SRSF1), impacting RNA binding and regulating alternative pre-mRNA splicing. This discovery reveals a new mechanism for AMPK in cellular energy homeostasis.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • AMP-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis, influencing metabolic pathways.
  • Metformin, an AMPK activator, has been shown to affect alternative pre-mRNA splicing.
  • No direct AMPK substrates involved in alternative pre-mRNA splicing were previously identified.

Purpose of the Study:

  • To identify direct substrates of AMPK involved in alternative pre-mRNA splicing.
  • To elucidate the mechanism by which AMPK influences pre-mRNA splicing.
  • To investigate the role of AMPK in regulating the splicing factor SRSF1.

Main Methods:

  • Phosphorylation site mapping of SRSF1 by AMPK.
  • RNA binding assays to assess SRSF1-RNA interactions.
  • Analysis of alternative pre-mRNA splicing of the Ron receptor.

Main Results:

  • Serine/arginine-rich splicing factor 1 (SRSF1) was identified as a direct AMPK substrate.
  • AMPK phosphorylates SRSF1 at Serine 133 within an RNA recognition motif.
  • Phosphorylation at Ser133 reduces SRSF1's interaction with specific RNA sequences, including exon 12 of Ron pre-mRNA.
  • AMPK-mediated SRSF1 phosphorylation regulates alternative splicing of the Ron receptor.

Conclusions:

  • AMPK directly phosphorylates SRSF1, inhibiting its RNA-binding capacity.
  • This phosphorylation event regulates alternative pre-mRNA splicing, specifically for the Ron receptor.
  • The findings reveal a novel mechanism linking AMPK activity to gene expression regulation through splicing factor modification.
Keywords:
AMPKSRSF1alternative splicingphosphorylation

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