Endotoxin stabilizes protein arginine methyltransferase 4 (PRMT4) protein triggering death of lung epithelia

• Published in: Cell death & disease 2021-09, Vol.12 (9), p.828-11, Article 828
• Main Authors: Lai, Yandong, Li, Xiuying, Li, Tiao, Nyunoya, Toru, Chen, Kong, Kitsios, Georgios D., Nouraie, Seyed Mehdi, Zhang, Yingze, McVerry, Bryan J., Lee, Janet S., Mallampalli, Rama K., Zou, Chunbin
• Format: Article
• Language: English
• Subjects: 631/337/176; 631/337/474/2073; 631/45/607/1166; 692/420/254; 96/2; 96/95; Acute Lung Injury - enzymology; Acute Lung Injury - pathology; Animal models; Animals; Antibodies; Apoptosis; Arginine; Biochemistry; Biodegradation; Biomedical and Life Sciences; Caspase 3 - metabolism; Caspase-3; Cell Biology; Cell Culture; Cell death; Cell Death - drug effects; Cell Line; Chromatin; Endotoxins - toxicity; Enzyme Activation - drug effects; Enzyme Stability - drug effects; Epigenetics; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - enzymology; Epithelial Cells - pathology; F-Box Proteins - metabolism; Humans; Immunology; Life Sciences; Life span; Lung - pathology; Lungs; Lysine - metabolism; Mice; Models, Biological; N-Methyltransferase; Phosphorylation - drug effects; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein arginine methyltransferase; Protein-Arginine N-Methyltransferases - metabolism; Proteins; Proteolysis - drug effects; Respiratory distress syndrome; Respiratory failure; Ubiquitin; Ubiquitin - metabolism; Ubiquitin-protein ligase; Ubiquitination - drug effects
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04115-7

Lung epithelial cell death is a prominent feature of acute lung injury and acute respiratory distress syndrome (ALI/ARDS), which results from severe pulmonary infection leading to respiratory failure. Multiple mechanisms are believed to contribute to the death of epithelia; however, limited data propose a role for epigenetic modifiers. In this study, we report that a chromatin modulator protein arginine N -methyltransferase 4/coactivator-associated arginine methyltransferase 1 (PRMT4/CARM1) is elevated in human lung tissues with pneumonia and in experimental lung injury models. Here PRMT4 is normally targeted for its degradation by an E3 ubiquitin ligase, SCF FBXO9 , that interacts with PRMT4 via a phosphodegron to ubiquitinate the chromatin modulator at K228 leading to its proteasomal degradation. Bacterial-derived endotoxin reduced levels of SCF FBXO9 thus increasing PRMT4 cellular concentrations linked to epithelial cell death. Elevated PRMT4 protein caused substantial epithelial cell death via caspase 3-mediated cell death signaling, and depletion of PRMT4 abolished LPS-mediated epithelial cell death both in cellular and murine injury models. These findings implicate a unique molecular interaction between SCF FBXO9 and PRMT4 and its regulation by endotoxin that impacts the life span of lung epithelia, which may play a key role in the pathobiology of tissue injury observed during critical respiratory illness.