AMPK regulates alternative pre-mRNA splicing by phosphorylation of SRSF1

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K15273
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Food science
• Research Institution: Tokyo University of Agriculture
• Principal Investigator: SUZUKI Tsukasa 東京農業大学, 応用生物科学部, 助教 (20714588)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: AMPK / SRSF1 / 選択的スプライシング

Outline of Final Research Achievements

AMPK regulates cellular energy homeostasis by inhibiting anabolic processes and activating catabolic processes. Recent studies have demonstrated that metformin, which is an AMPK activator, modifies alternative pr-mRNA splicing. However, no direct substrate of AMPK for alternative pre-mRNA splicing has been reported. In this study, we identified the splicing factor SRSF1 as a novel AMPK substrate. AMPK directly phosphorylated SRSF1 at Ser133 in an RNA recognition motif. Ser133 phosphorylation suppressed the interaction between SRSF1 and specific RNA sequences without altering the subcellular localization of SRSF1. Moreover, AMPK regulated the SRSF1-mediated alternative pre-mRNA splicing of Ron, which is a macrophage-stimulating protein receptor, by suppressing its interaction with exon 12 of Ron pre-mRNA. The findings of this study revealed that the AMPK-dependent phosphorylation of SRSF1 at Ser133 inhibited the ability of SRSF1 to bind RNA and regulated alternative pre-mRNA splicing.

Free Research Field

栄養生化学

Academic Significance and Societal Importance of the Research Achievements

AMPKが関与するSRSF1の新たな翻訳後修飾を明らかにしたことによって、SRSF1依存的な選択的スプライシング制御をより詳細なレベルで理解することができる。これにより選択的スプライシングの破綻による疾病の発症機序の理解、そして遺伝性疾患において、変異したエクソンをスキップさせて正常に近いタンパク質を発現させる、エクソンスキッピングと呼ばれる治療法に対する新しいアプローチにもつながる。また、これらの疾患にAMPK活性化剤や阻害剤、そして栄養状態の管理などの手法を用いる応用研究にもつながる。