Department of Biological Chemistry, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Cell Rep. 2023 May 30;42(5):112411. doi: 10.1016/j.celrep.2023.112411. Epub 2023 Apr 21.
Cellular metabolism is tightly regulated by growth factor signaling, which promotes metabolic rewiring to support growth and proliferation. While growth factor-induced transcriptional and post-translational modes of metabolic regulation have been well defined, whether post-transcriptional mechanisms impacting mRNA stability regulate this process is less clear. Here, we present the ZFP36/L1/L2 family of RNA-binding proteins and mRNA decay factors as key drivers of metabolic regulation downstream of acute growth factor signaling. We quantitatively catalog metabolic enzyme and nutrient transporter mRNAs directly bound by ZFP36 following growth factor stimulation-many of which encode rate-limiting steps in metabolic pathways. Further, we show that ZFP36 directly promotes the mRNA decay of Enolase 2 (Eno2), altering Eno2 protein expression and enzymatic activity, and provide evidence of a ZFP36/Eno2 axis during VEGF-stimulated developmental retinal angiogenesis. Thus, ZFP36-mediated mRNA decay serves as an important mode of metabolic regulation downstream of growth factor signaling within dynamic cell and tissue states.
细胞代谢受到生长因子信号的严格调控，促进代谢重编程以支持生长和增殖。虽然生长因子诱导的代谢调节的转录和翻译后模式已经得到很好的定义，但影响 mRNA 稳定性的转录后机制是否调节这个过程还不太清楚。在这里，我们提出 ZFP36/L1/L2 家族的 RNA 结合蛋白和 mRNA 降解因子作为急性生长因子信号下游代谢调节的关键驱动因素。我们定量编目了 ZFP36 在生长因子刺激后直接结合的代谢酶和营养转运体 mRNA——其中许多编码代谢途径中的限速步骤。此外，我们还表明 ZFP36 直接促进烯醇酶 2 (Eno2) 的 mRNA 降解，改变 Eno2 蛋白表达和酶活性，并提供了在 VEGF 刺激的发育性视网膜血管生成过程中 ZFP36/Eno2 轴的证据。因此，ZFP36 介导的 mRNA 降解是生长因子信号下游在动态细胞和组织状态下代谢调节的重要模式。
