2. Academic Validation
  3. TRIM14 inhibits OPTN-mediated autophagic degradation of KDM4D to epigenetically regulate inflammation

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

  • Proc Natl Acad Sci U S A. 2022 Feb 15;119(7):e2113454119. doi: 10.1073/pnas.2113454119.
Di Liu 1,  Zhiyao Zhao 1 2,  Yuanchu She 1,  Lei Zhang 1,  Xiangtian Chen 1,  Ling Ma 1,  Jun Cui 3
Affiliations

Affiliations

  • 1 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangdong 510275, People's Republic of China.
  • 2 Department of Internal Medicine, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangdong 510623, People's Republic of China.
  • 3 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangdong 510275, People's Republic of China; cuij5@mail.sysu.edu.cn.
PMID: 35145029 DOI: 10.1073/pnas.2113454119
Abstract

Autophagy is a fundamental cellular process of protein degradation and recycling that regulates immune signaling pathways via multiple mechanisms. However, it remains unclear how Autophagy epigenetically regulates the immune response. Here, we identified TRIM14 as an 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 optineurin (OPTN)-mediated selective Autophagy. Tripartite motif-containing 14 (TRIM14) deficiency in dendritic cells significantly impaired the expression of the KDM4D-directed proinflammatory cytokines interleukin 12 (Il12) and Il23 and protected mice from autoimmune inflammation. Taken together, these findings highlight the cross-talk between epigenetic regulation and Autophagy and suggest TRIM14 is a potential target of therapeutic intervention for inflammation-related diseases.

Keywords

KDM4D; TRIM14; autophagy; epigenetic regulation; inflammation.

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