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

Abstract

Significance Histone methylation regulates gene transcription through a variety of methylases and demethylases. The regulatory role of autophagy, an important process of protein degradation and recycling, in these histone modifiers is still unclear. We report that TRIM14 stabilized the histone demethylase KDM4D to facilitate the transcription of interleukin 12 ( Il12 ) and Il23 by inhibiting histone H3K9 trimethylation in vitro and in vivo. Mechanistically, TRIM14 recruited the deubiquitinases USP14 and BRCC3 to remove the K63-linked ubiquitin chains of KDM4D and prevented it from undergoing optineurin-mediated autophagic degradation. This study is valuable not only for increasing our understanding of the cross-talk between autophagy and epigenetic regulation, but also for demonstrating the potential of TRIM14 as a target for therapeutic interventions for inflammation-related diseases.