hnRNP L-mediated RNA switches function as a hypoxia-induced translational regulon.
hnRNP L-mediated RNA switches function as a hypoxia-induced translational regulon.
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DOI：
10.1016/j.bbrc.2019.06.106
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发表时间：
2019-08
影响因子：
3.1
通讯作者：
K. V. Venkata Subbaiah;Jiangbin Wu;Alka A. Potdar;Peng Yao
中科院分区：
文献类型：
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作者：
K. V. Venkata Subbaiah;Jiangbin Wu;Alka A. Potdar;Peng Yao
GAIT（γ-干扰素激活的翻译抑制剂）复合物或miR-297-RISC（RNA诱导的沉默复合物）与hnRNP L或携带hnRNP L的复合物一起在骨髓细胞中操作RNA开关，其调节血管内皮生长因子-A（VEGFA）的应激依赖性表达。在这里，我们已经表明，hnRNP L指导多个缺氧诱导的RNA开关同时和调节这些致癌基因的表达，除了VEGFA。生物信息学和多核糖体分析-微阵列筛选已鉴定DNM 1 L（发动蛋白1样）和PHF 21 A（PHD指蛋白21 A）mRNA在翻译水平上受GAIT依赖性、hnRNP L指导的RNA开关调控。我们还发现了CDK 6（细胞周期蛋白依赖性激酶6）、MKLN 1（Muskelin 1）和EIF 5（真核起始因子5）作为新的miR-297依赖性、hnRNP L指导的RNA开关转录物。Src激酶是hnRNP L磷酸化和RNA开关途径激活所必需的。敲低hnRNP L可使人U937单核细胞在低氧应激下敏感，但在常氧条件下不敏感，这部分是由于hnRNP L靶mRNA翻译减少而诱导细胞凋亡。总的来说，我们的研究结果表明，共同控制的基因hnRNP L-定向RNA开关形成一个翻译调节子，促进耐缺氧和细胞存活。
The GAIT (gamma-interferon-activated inhibitor of translation) complex or miR-297-RISC (RNA-induced silencing complex), together with hnRNP L or hnRNP L-bearing complex, operates an RNA switch in myeloid cells that regulates stress-dependent expression of vascular endothelial growth factor-A (VEGFA). Here, we have shown that hnRNP L directs multiple hypoxia-inducible RNA switches simultaneously and regulates expression of these oncogenic genes in addition to VEGFA. Bioinformatic and polysome profiling-microarray screens have identifiedDNM1L(Dynamin 1-like) andPHF21A(PHD finger protein 21A) mRNAs as regulated at the translational level by GAIT-dependent, hnRNP L-directed RNA switches. We have also uncoveredCDK6(Cyclin dependent kinase 6),MKLN1(Muskelin 1) andEIF5(Eukaryotic initiation factor 5) as novel miR-297-dependent, hnRNP L-directed RNA switch transcripts. Src Kinase is required for the phosphorylation of hnRNP L and activation of the RNA switch pathway. Knockdown of hnRNP L sensitizes the human U937 monocytic cells under hypoxia stress but not in normoxia via inducing cell apoptosis partially due to the reduced translation of hnRNP L target mRNAs. Collectively, our findings suggest that commonly controlled genes by the hnRNP L-directed RNA switches form a translational regulon that promotes hypoxia resistance and cell survival.