AMP-activated protein kinase regulates alternative pre-mRNA splicing by phosphorylation of SRSF1
AMP-activated protein kinase regulates alternative pre-mRNA splicing by phosphorylation of SRSF1
复制标题
AMP 激活蛋白激酶通过 SRSF1 磷酸化调节选择性前 mRNA 剪接
DOI：
10.1042/bcj20190894
复制
发表时间：
2020
影响因子：
4.1
通讯作者：
Suzuki Tsukasa
中科院分区：
文献类型：
--
作者：
Matsumoto Eri;Akiyama Kaho;Saito Takuya;Matsumoto Yu;Kobayashi Ken-Ichi;Inoue Jun;Yamamoto Yuji;Suzuki Tsukasa
AMP激活蛋白激酶（AMPK）通过抑制合成代谢过程和激活分解代谢过程来调节细胞能量稳态。最近的研究表明，二甲双胍，这是一种AMPK激活剂，修改替代前体mRNA（前mRNA）剪接。然而，没有直接底物AMPK的选择性前mRNA剪接已被报道。在本研究中，我们确定了剪接因子丝氨酸/丝氨酸丰富的剪接因子1（SRSF 1）作为一种新的AMPK底物。AMPK直接磷酸化RNA识别基序中Ser 133处的SRSF 1。Ser 133磷酸化抑制SRSF 1和特定RNA序列之间的相互作用，而不改变SRSF 1的亚细胞定位。此外，AMPK通过抑制SRSF 1与罗恩前体mRNA外显子12的相互作用，调节SRSF 1介导的罗恩（巨噬细胞刺激蛋白受体）前体mRNA的选择性剪接。本研究的结果表明，AMPK依赖的SRSF 1的Ser 133磷酸化抑制SRSF 1结合RNA的能力和调节选择性前mRNA剪接。
AMP-activated protein kinase (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 precursor mRNA (pre-mRNA) splicing. However, no direct substrate of AMPK for alternative pre-mRNA splicing has been reported. In the present study, we identified the splicing factor serine/arginine-rich splicing factor 1 (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.