Abstract
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.
Highlights
The JAK-STAT pathway mediates important biological mechanisms, including inflammation, cell proliferation and antiviral activity, and is stimulated by receptor binding of cytokines, such as IFNs and IL-6 [1,2]
We identified 12 protein coding genes associated with the JAK-STAT pathway to contain miR-19a target sequences in their 3’UTR (Table 1)
We found that the entire 3’UTR of these genes and each of the these regulatory miR-19a binding site genes were conserved across several species, including chimpanzee (Ptr), rhesus (Mml), dog (Cfa), mouse (Mmu) and horse (Eca) (Figure 1B), strongly indicating a precise and important role for miR-19a in the regulation of JAKSTAT pathway components
Summary
The JAK-STAT pathway mediates important biological mechanisms, including inflammation, cell proliferation and antiviral activity, and is stimulated by receptor binding of cytokines, such as IFNs and IL-6 [1,2]. SOCS proteins silence the pathway by acting as pseudo-substrates that block JAK kinase ability, binding to the receptor to prevent STAT interaction and targeting proteins for proteasomal degradation [5]. SOCS form Elongin C-Cullin–SOCS box (ECS)-type complexes that function as E3 ubiquitin ligases and target specific proteins for ubiquitin-mediated degradation. This is achieved when Elongin B binds Elongin C, which bridges the substrate recognised by the SOCS protein to a Cul scaffold protein [6]. SOCS3 targets receptors for proteasomal degradation following association with Cul and Elongin BC [7]
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