Yao Peng, Wu Jiangbin, Lindner Daniel, Fox Paul L
Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA.
Nucleic Acids Res. 2017 Jul 27;45(13):7950-7964. doi: 10.1093/nar/gkx440.
MicroRNAs (miRNAs) and heterogeneous nuclear ribonucleoproteins (hnRNPs) are families of sequence-specific, posttranscriptional modulators of gene expression. Despite extensive mechanistic and functional studies on both regulatory classes, the interactions and crosstalk between them are largely unexplored. We have reported that competition between miR-297 and hnRNP L to bind a 3΄UTR-localized CA-rich element (CARE) of VEGFA mRNA regulates its translation. Here, we show that translation of VEGFA mRNA in human myeloid cells is dictated by a bi-directional interaction between miR-574-3p, a CA-rich microRNA, and hnRNP L. In normoxia, miR-574-3p, acting as a decoy, binds cytoplasmic hnRNP L and prevents its binding to the CARE and stimulation of VEGFA mRNA translation, simultaneously permitting miR-297-mediated translational silencing. However, in hypoxia, cytoplasmic accumulation of Tyr359-phosphorylated hnRNP L sequesters miR-574-3p, overcoming its decoy activity and seed sequence-dependent gene silencing activity. Ectopically expressed miR-574-3p binds multiple RNA recognition motif (RRM) domains of hnRNP L, synergizes with miR-297, reduces VEGFA mRNA translation, and triggers apoptosis, thereby suppressing tumorigenesis. Our studies establish a novel condition-dependent interplay between a miRNA and an hnRNP that regulates their functions in a bidirectional manner.
微小RNA（miRNA）和不均一核核糖核蛋白（hnRNP）是基因表达的序列特异性转录后调节因子家族。尽管对这两类调节因子进行了广泛的机制和功能研究，但它们之间的相互作用和串扰在很大程度上仍未得到探索。我们曾报道，miR-297与hnRNP L竞争结合VEGFA mRNA的3΄非翻译区（UTR）定位的富含CA元件（CARE），从而调节其翻译。在此，我们表明，人类髓系细胞中VEGFA mRNA的翻译由富含CA的微小RNA miR-574-3p与hnRNP L之间的双向相互作用决定。在常氧条件下，miR-574-3p作为诱饵，结合细胞质中的hnRNP L，阻止其与CARE结合并刺激VEGFA mRNA的翻译，同时允许miR-297介导的翻译沉默。然而，在缺氧条件下，酪氨酸359磷酸化的hnRNP L在细胞质中积累，隔离miR-574-3p，克服其诱饵活性和种子序列依赖性基因沉默活性。异位表达的miR-574-3p结合hnRNP L的多个RNA识别基序（RRM）结构域，与miR-297协同作用，减少VEGFA mRNA的翻译，并触发细胞凋亡，从而抑制肿瘤发生。我们的研究建立了一种新的miRNA与hnRNP之间的条件依赖性相互作用，这种相互作用以双向方式调节它们的功能。
