Amen Alexandra M, Ruiz-Garzon Claudia R, Shi Jay, Subramanian Megha, Pham Daniel L, Meffert Mollie K
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mol Cell. 2017 Feb 2;65(3):490-503.e7. doi: 10.1016/j.molcel.2016.12.025. Epub 2017 Jan 26.
Environmental cues provoke rapid transitions in gene expression to support growth and cellular plasticity through incompletely understood mechanisms. Lin28 RNA-binding proteins have evolutionarily conserved roles in post-transcriptional coordination of pro-growth gene expression, but signaling pathways allowing trophic stimuli to induce Lin28 have remained uncharacterized. We find that Lin28a protein exhibits rapid basal turnover in neurons and that mitogen-activated protein kinase (MAPK)-dependent phosphorylation of the RNA-silencing factor HIV TAR-RNA-binding protein (TRBP) promotes binding and stabilization of Lin28a, but not Lin28b, with an accompanying reduction in Lin28-regulated miRNAs, downstream of brain-derived neurotrophic factor (BDNF). Binding of Lin28a to TRBP in vitro is also enhanced by phospho-mimic TRBP. Further, phospho-TRBP recapitulates BDNF-induced neuronal dendritic spine growth in a Lin28a-dependent manner. Finally, we demonstrate MAPK-dependent TRBP and Lin28a induction, with physiological function in growth and survival, downstream of diverse growth factors in multiple primary cell types, supporting a broad role for this pathway in trophic responses.
环境线索通过尚未完全了解的机制引发基因表达的快速转变，以支持生长和细胞可塑性。Lin28 RNA结合蛋白在促进生长基因表达的转录后协调中具有进化上保守的作用，但允许营养刺激诱导Lin28的信号通路仍未得到表征。我们发现，Lin28a蛋白在神经元中表现出快速的基础周转，并且RNA沉默因子HIV TAR-RNA结合蛋白（TRBP）的丝裂原活化蛋白激酶（MAPK）依赖性磷酸化促进了Lin28a（而非Lin28b）的结合和稳定，同时伴随着脑源性神经营养因子（BDNF）下游Lin28调节的微小RNA的减少。磷酸化模拟TRBP也增强了Lin28a在体外与TRBP的结合。此外，磷酸化TRBP以Lin28a依赖性方式重现了BDNF诱导的神经元树突棘生长。最后，我们证明了在多种原代细胞类型中，多种生长因子下游存在MAPK依赖性的TRBP和Lin28a诱导，且在生长和存活中具有生理功能，这支持了该通路在营养反应中的广泛作用。
