Fine-tuning type I IFN signaling: A new chapter in the IFN saga

Abstract

Type I interferon (IFN) signaling is critical for intracellular antimicrobial programmes, affecting both innate and adaptive immune responses. The paper recently published in Cell demonstrates a new regulatory mechanism of the type I IFN signaling pathway by histone-lysine N-methyltransferase SETD2.The Janus tyrosine kinase (JAK), Signal Transducer and Activator of Transcription (STAT) proteins, and Interferon Regulatory Factor (IRF) family of transcription factors are important mediators of many cytokine systems [1][2][3][4]. While cytokine research has impacted a number of fields, it is remarkable that the major cytokine pathways were first elucidated in the context of the same regulatory network, the type I interferon (IFN) system. As such, one may term the series of studies as a first wave of research on cytokine induction and action.The field may now be witnessing a so-called second wave of discovery related to how cytokine signaling systems are fine-tuned by other regulatory pathways. This is exemplified by a recent paper by Cao laboratory who demonstrate that type I IFN-induced STAT1 activation is regulated by histone-lysine N-methyltransferase SETD2 (SET domain containing 2), which has been previously characterized for its trimethylation of lysine 36 of histone H3 (H3K36) [5]. The authors first performed high-throughput screening of epigenetic modifiers by lentivirusmediated RNAi (RNA interference) to search for epigenetic factors that modu-

PRC2 activates interferon-stimulated genes indirectly by repressing miRNAs in glioblastoma

“…Conversely, we show that PRC2 activates ISGs by repressing miRNAs that target them, suggesting that PRC2 can both activate as well as repress expression of ISGs. A similar dual regulatory impact on interferon pathway genes was previously observed for SETD2 histone methyltransferase (22). It is possible that, like SETD2, PRC2 also functions in the finetuning of interferon response.…”

PRC2 activates interferon-stimulated genes indirectly by repressing miRNAs in glioblastoma

“…Conversely, we show that PRC2 activates ISGs by repressing miRNAs that target them, suggesting that PRC2 can both activate as well as repress expression of ISGs. A similar dual regulatory impact on interferon pathway genes was previously observed for SETD2 histone methyltransferase [25]. It is possible that, like SETD2, PRC2 also functions in the fine-tuning of interferon response.…”

Analysis of transcriptomic changes in bovine endometrial stromal cells treated with lipopolysaccharide

“…The expression of these cytokines was also upregulated in only epithelial cells, only stromal cells, and mixed epithelial and stromal cells treated with LPS in vitro [12,19,25]. On the other hand, activation of PRR also triggers many signal transduction pathways through one or more of the IRF family of transcription factors, leading to the expression of IFNs [26]. LPS upregulated the expression IFN-stimulated genes (ISG) including RSAD2, MX2, OAS1Y, ISG15, and BST2 in mixed epithelial and stromal cells [19].…”