TRIM14 inhibits OPTN-mediated autophagic degradation of KDM4D to epigenetically regulate inflammation

Autophagy is a fundamental cellular process of protein degradation and recycling that regulates immune signalling pathways via multiple mechanisms. However, it remains unclear how autophagy epigenetically regulates the immune response. Here, we identified TRIM14 as a novel epigenetic regulator that reduces histone H3K9 trimethylation by inhibiting the autophagic degradation of the histone demethylase KDM4D. TRIM14 recruited the deubiquitinases USP14 and BRCC3 to cleave the K63-linked ubiquitin chains of KDM4D, which prevented KDM4D from undergoing OPTN-mediated selective autophagy. TRIM14 deficiency in dendritic cells significantly impaired the expression of the KDM4D-directed proinflammatory cytokines Il12 and Il23 and protected mice from autoimmune inflammation. Taken together, these findings highlight the crosstalk between epigenetic regulation and autophagy and suggest TRIM14 is a potential target of therapeutic intervention for inflammation-related diseases.