Sjogren Syndrome Antigen B (SSB)/La Promotes Global MicroRNA Expression by Binding MicroRNA Precursors through Stem-Loop Recognition
Sjogren Syndrome Antigen B (SSB)/La Promotes Global MicroRNA Expression by Binding MicroRNA Precursors through Stem-Loop Recognition
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DOI：
10.1074/jbc.m112.401323
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发表时间：
2013-01-04
影响因子：
4.8
通讯作者：
Liu, Qinghua
中科院分区：
文献类型：
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作者：
Liang, Chunyang;Xiong, Ke;Liu, Qinghua
MicroRNAs （miRNA）控制着许多生理和病理过程。通常，初级miRNA （pri-miRNA）转录本被核Drosha复合体加工成类似于70个核苷酸的茎环前体miRNA (pre-miRNA)，其进一步被细胞质Dicer复合体切割成类似于21个核苷酸的成熟miRNA。然而，尚不清楚新生的pre-miRNA是如何免受核糖核酸酶（如MCPIP1）的保护的，核糖核酸酶会降解pre-miRNA，从而中止miRNA的产生。在这里，我们确定干燥综合征抗原B (SSB)/La作为miRNA前结合蛋白，在体外调节miRNA加工。La/SSB的所有三个rna结合基序（LAM、RRM1和RRM2）都是有效结合pre-miRNA所必需的。有趣的是，La/SSB识别了pre- mirna的特征茎环结构，其中大多数缺乏3' UUU末端。此外，La/SSB与内源性pri-/pre-miRNA结合，并通过稳定哺乳动物细胞中核酸酶（如MCPIP1）介导的衰变的pre-miRNA来促进miRNA的生物发生。因此，我们观察到La/SSB和Dicer在人类癌症转录组中的表达状态与预后呈正相关。这些研究确定了La/SSB作为miRNA表达的全局调节剂的重要功能，并暗示茎环识别是介导La/SSB与多种RNA分子之间关联的主要机制。
MicroRNAs (miRNA) control numerous physiological and pathological processes. Typically, the primary miRNA (pri-miRNA) transcripts are processed by nuclear Drosha complex into similar to 70-nucleotide stem-loop precursor miRNAs (pre-miRNA), which are further cleaved by cytoplasmic Dicer complex into similar to 21-nucleotide mature miRNAs. However, it is unclear how nascent pre-miRNAs are protected from ribonucleases, such as MCPIP1, that degrade pre-miRNAs to abort miRNA production. Here, we identify Sjogren syndrome antigen B (SSB)/La as a pre-miRNA-binding protein that regulates miRNA processing in vitro. All three RNA-binding motifs (LAM, RRM1, and RRM2) of La/SSB are required for efficient pre-miRNA binding. Intriguingly, La/SSB recognizes the characteristic stem-loop structure of pre-miRNAs, of which the majority lack a 3' UUU terminus. Moreover, La/SSB associates with endogenous pri-/pre-miRNAs and promotes miRNA biogenesis by stabilizing pre-miRNAs from nuclease (e.g. MCPIP1)-mediated decay in mammalian cells. Accordingly, we observed positive correlations between the expression status of La/SSB and Dicer in human cancer transcriptome and prognosis. These studies identify an important function of La/SSB as a global regulator of miRNA expression, and implicate stem-loop recognition as a major mechanism that mediates association between La/SSB and diverse RNA molecules.