School of Biochemistry and Immunology, Trinity College, University of Dublin, Dublin, Ireland.
PLoS One. 2013 Jul 22;8(7):e69090. doi: 10.1371/journal.pone.0069090. Print 2013.
Suppressors of cytokine signalling (SOCS) proteins are classic inhibitors of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Many cytokines and pathogenic mediators induce expression of SOCS, which act in a negative feedback loop to inhibit further signal transduction. SOCS mRNA expression is regulated by DNA binding of STAT proteins, however, their post-transcriptional regulation is poorly understood. microRNAs (miRNAs) are small non-coding RNAs that bind to complementary sequences on target mRNAs, often silencing gene expression. miR-19a has been shown to regulate SOCS1 expression during mutiple myeloma and be induced by the anti-viral cytokine interferon-(IFN)-α, suggesting a role in the regulation of the JAK-STAT pathway. This study aimed to identify targets of miR-19a in the JAK-STAT pathway and elucidate the functional consequences. Bioinformatic analysis identified highly conserved 3'UTR miR-19a target sequences in several JAK-STAT associated genes, including SOCS1, SOCS3, SOCS5 and Cullin (Cul) 5. Functional studies revealed that miR-19a significantly decreased SOCS3 mRNA and protein, while a miR-19a antagomir specifically reversed its inhibitory effect. Furthermore, miR-19a-mediated reduction of SOCS3 enhanced IFN-α and interleukin (IL)-6 signal transduction through STAT3. These results reveal a novel mechanism by which miR-19a may augment JAK-STAT signal transduction via control of SOCS3 expression and are fundamental to the understanding of inflammatory regulation.
细胞因子信号转导抑制蛋白（SOCS）是 Janus 激酶-信号转导和转录激活因子（JAK-STAT）通路的经典抑制剂。许多细胞因子和致病介质诱导 SOCS 的表达，SOCS 作为负反馈环的一部分，抑制进一步的信号转导。SOCS mRNA 的表达受 STAT 蛋白的 DNA 结合调节，但它们的转录后调节知之甚少。microRNAs（miRNAs）是一种小的非编码 RNA，可与靶 mRNA 上的互补序列结合，通常抑制基因表达。miR-19a 已被证明在多发性骨髓瘤中调节 SOCS1 的表达，并被抗病毒细胞因子干扰素-α（IFN-α）诱导，提示其在 JAK-STAT 通路调节中的作用。本研究旨在鉴定 miR-19a 在 JAK-STAT 通路中的靶标，并阐明其功能后果。生物信息学分析在几种 JAK-STAT 相关基因中鉴定出高度保守的 3'UTR miR-19a 靶序列，包括 SOCS1、SOCS3、SOCS5 和 Cullin（Cul）5。功能研究表明，miR-19a 显著降低 SOCS3 mRNA 和蛋白水平，而 miR-19a 拮抗剂则特异性逆转其抑制作用。此外，miR-19a 介导的 SOCS3 减少增强了 IFN-α 和白细胞介素（IL）-6 通过 STAT3 的信号转导。这些结果揭示了 miR-19a 通过控制 SOCS3 表达来增强 JAK-STAT 信号转导的新机制，对炎症调节的理解具有重要意义。
