Histone Methyltransferase Ash1l Suppresses Interleukin-6 Production and Inflammatory Autoimmune Diseases by Inducing the Ubiquitin-Editing Enzyme A20

Abstract

Histone modifications play important roles in multiple physiological processes by regulating gene expression. However, the roles of histone modifications in immunity remain poorly understood. Here we report that Ash1l, a H3K4 methyltransferase, suppressed interleukin-6 (IL-6), and tumor necrosis factor (TNF) production in Toll-like receptor (TLR)-triggered macrophages, protecting mice from sepsis. Ash1l-silenced mice were more susceptible to autoimmune disease as a result of enhanced IL-6 production. Ash1l enhanced A20 expression through induction of H3K4 modification at the Tnfaip3 promoter via H3K4 methyltransferase activity of Ash1l SET (Su[var]3-9, E[z] and trithorax) domain. Ash1l suppressed NF-κB, mitogen-activated protein kinase (MAPK) pathways, and subsequent IL-6 production via facilitating A20-mediated NF-κB signal modulator NEMO and transducer TRAF6 deubiquitination. Therefore, Ash1l-mediated H3K4 methylation at the Tnfaip3 promoter is required for controlling innate IL-6 production and suppressing inflammatory autoimmune diseases, providing mechanistic insight into epigenetic modulation of immune responses and inflammation.

Cellular and molecular regulation of innate inflammatory responses

“…77 In addition, histone methyltransferase Ash1l binds to the promoter regions of A20 gene to enhance the H3K4 methylation level, thus inducing A20 gene transcription and expression, consequently suppressing TLR signaling and inflammatory autoimmune diseases. 78 These studies further highlight the importance of crosstalk between PTM and chromatin modification in innate immune signaling regulation.…”

Stk38 protein kinase preferentially inhibits TLR9-activated inflammatory responses by promoting MEKK2 ubiquitination in macrophages

“…Many molecules have been found to negatively regulate TLR signalling, ranging from extracellular decoy receptors to intracellular inhibitors 12 . In a recent study, histone methyltransferase Ash1l was found to suppress TLR-triggered inflammatory cytokine production and Ash1l-silenced mice were more susceptible to autoimmune disease 13 . Although intensively studied, the mechanisms by which TLR signal transduction is activated and regulated have not yet been fully understood.…”

Histone Lysine Methyltransferase Ezh1 Promotes TLR-Triggered Inflammatory Cytokine Production by Suppressing Tollip

“…Ezh2 also was found to specifically enhance Th cell differentiation and plasticity via transcriptional regulation of other lineage-specifying genes (17). Ashl1, a histone H3 lysine 4 methyltransferase, could induce A20 expression to suppress IL-6 production in inflammatory autoimmune diseases (18). However, the precise roles and the underlying mechanisms of the epigenetic molecules in the regulation of the inflammatory innate response remain to be fully investigated.…”