The methyltransferase NSD3 promotes antiviral innate immunity via direct lysine methylation of IRF3

Abstract

Wang et al. demonstrate that methyltransferase NSD3 directly methylates IRF3 and maintains IRF3 phosphorylation to enhance its transcriptional activity by disassociating the methylated IRF3 and PP1cc to prevent IRF3 dephosphorylation, consequently promoting antiviral innate immune response.

Enterovirus pathogenesis requires the host methyltransferase SETD3

“…Thus, SETD3 is an essential host factor that is broadly required for infection by viruses from the human enterovirus genus. SETD3 belongs to a class of protein methyltransferases containing the catalytic SET domain that has recently been linked to antiviral immunity mediated by interferon (IFN) 15,16 . Thus, to determine if the mechanism of action of viral resistance in SETD3 KO cells is through an upregulation of IFN-stimulated genes (ISGs), we first performed transcriptome-wide RNA sequencing in uninfected WT and SETD3 KO cells.…”

“…Recently, non-catalytic functions have been described for other SET-domain containing methyltransferases 34 and our results suggest that enteroviruses co-opted SETD3 by exploiting a non-catalytic function. Thus, the finding that a methyltransferase acts as a pro-viral host factor for the pathogenesis of a large class of viruses provides an interesting insight into how viruses must engage particular methyltransferases for viral replication and spread, while also being limited by related methyltransferases that promote antiviral immunity 15,16 . This emphasizes a largely unexplored and underappreciated role of host methyltransferases in viral pathogenesis.…”

Noncanonical Role of FBXO6 in Regulating Antiviral Immunity

“…Furthermore, Phosphatase and tensin homolog (PTEN) with phosphatase activity can negatively regulate IRF3 phosphorylation at Ser-97 to block its import to nucleus (12). In addition to phosphorylation, nuclear receptor-binding SET domain 3 (NSD3) has been identified as the lysine methyltransferase that methylate IRF3 at K366, enhancing the transcription activity of IRF3 (13).…”

NSD3 keeps IRF3 active

“…To identify methyltransferases mediating the K366-monomethylation of IRF3, the Wang et al (2017) performed coimmunoprecipitation and mass spectrometry analysis. They found that a lysine methyltransferase, NSD3, directly binds to IRF3.…”

“…It is interesting to speculate that the activity of NSD3 to methylate IRF3 is also dynamically controlled by viral infection. Wang et al (2017) subsequently investigated mechanisms of how the NSD3-mediated IRF3 methylation regulates IRF3 activity. Interestingly, VSV-induced IRF3 phosphorylation at Ser388 requires NSD3, and NSD3-mediated IRF3 methylation suppressed the interaction of IRF3 with protein phosphatase 1 (PP1), which is involved in the regulation of IRF3 activity via dephosphorylation (Gu et al, 2014).…”