F-Box Protein FBXW17-Mediated Proteasomal Degradation of Protein Methyltransferase PRMT6 Exaggerates CSE-Induced Lung Epithelial Inflammation and Apoptosis

Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic debilitating lung disease, characterized by progressive airway inflammation and lung structural cell death. Cigarette smoke is considered the most common risk factor of COPD pathogenesis. Understanding the molecular mechanisms of persistent inflammation and epithelial apoptosis induced by cigarette smoke would be extremely beneficial for improving the treatment and prevention of COPD. A histone methyl modifier, protein arginine N-methyltransferase 6 (PRMT6), is reported to alleviate cigarette smoke extract (CSE)-induced emphysema through inhibiting inflammation and cell apoptosis. However, few studies have focused on the modulation of PRMT6 in regulating inflammation and cell apoptosis. In this study, we showed that protein expression of PRMT6 was aberrantly decreased in the lung tissue of COPD patients and CSE-treated epithelial cells. FBXW17, a member of the Skp1-Cullin-F-box (SCF) family of E3 ubiquitin ligases, selectively bound to PRMT6 in nuclei to modulate its elimination in the proteasome system. Proteasome inhibitor or silencing of FBXW17 abrogated CSE-induced PRMT6 protein degradation. Furthermore, negative alteration of FBXW17/PRMT6 signaling lessened the proapoptotic and proinflammatory effects of CSE in lung epithelial cells. Our study, therefore, provides a potential therapeutic target against the airway inflammation and cell death in CS-induced COPD.

Prmt6 represses the pro-adipogenic Ppar-gamma–C/ebp-alpha transcription factor loop

“…Alternatively, Prmt6 transcript stability could be regulated by RNA-methylation as was recently described for Prmt6 28 . There is also evidence for regulation of Prmt6 by proteasomal degradation 29 , 30 . In our hands, treatment of proteasome inhibitor MG132 did not lead to an increased Prmt6 protein level in ST2 cells (Supplemental Figure S3 ).…”

MFG-E8 stabilized by deubiquitinase USP14 suppresses cigarette smoke-induced ferroptosis in bronchial epithelial cells

“…Kim et al reported that CSE induced Akt ubiquitination and proteasomal degradation through promoting ubiquitin E3 ligase expression, which led to cell death in normal human lung fibroblasts [ 25 ]. Recently, Li et al found that F-box protein FBXW17, an E3 ubiquitin ligase, exaggerated CSE-induced lung epithelial inflammation and apoptosis via mediating the proteasomal degradation of protein methyltransferase PRMT6 [ 3 ]. However, the expression of deubiquitinase USP17 in CSE-exposed airway epithelial cells was downregulated, resulting in the degradation of histone deacetylase HDAC2 by ubiquitination and glucocorticoid resistance in COPD [ 26 ].…”

“…The airway epithelium is the first line of defense against pathogens and harmful particles inhaled into the lungs. Airway epithelial cell dysfunction and programmed cell death induced by cigarette smoke take part in the pathogenesis of COPD [ 2 , 3 ].…”

Structure, Activity and Function of the Protein Arginine Methyltransferase 6

“…PRMT6 is expressed in a wide range of tissues with high expression in kidney and testes [ 44 ]. The F-box proteins, FBXO24 and FBXW17, regulate the protein levels of PRMT6 by facilitating its proteasomal degradation [ 45 , 46 ]. PRMT6 generates asymmetric dimethylation modifications in histone 3 at arginine 2, arginine 17 and arginine 42 (H3R2me2a, H3R17me2a and H3R42me2a) [ 4 , 5 , 6 , 47 , 48 ] and in histone H2A at arginine 26 (H2AR26me2a) [ 49 ] and participates in the epigenetic regulation of gene expression.…”