miR-19a: an effective regulator of SOCS3 and enhancer of JAK-STAT signalling

• Published in: PloS one 2013-07, Vol.8 (7), p.e69090-e69090
• Main Authors: Collins, Aideen S, McCoy, Claire E, Lloyd, Andrew T, O'Farrelly, Cliona, Stevenson, Nigel J
• Format: Article
• Language: English
• Subjects: 3' Untranslated regions; Antiviral agents; B cells; Base Sequence; Binding sites; Biochemistry; Biological response modifiers; Cancer; Cell adhesion & migration; Cell cycle; Cell Line; Cellular signal transduction; Control theory; Cullin; Cytokines; Deoxyribonucleic acid; DNA; Feedback loops; Gene expression; Gene regulation; Gene sequencing; Genes; Humans; Immunology; Inflammation; Interferon; Interferon-alpha - pharmacology; Interleukin; Interleukin-1 - pharmacology; Interleukins; Janus kinase; Janus Kinases - metabolism; Kinases; MicroRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Multiple myeloma; Myeloma; Negative feedback; Porphyromonas gingivalis; Post-transcription; Protein binding; Proteins; Reproducibility of Results; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Signaling; STAT Transcription Factors - metabolism; Stat3 protein; Studies; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressors; Target recognition; Transcription (Genetics); Transduction; α-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0069090

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.