B65-07 Activation of USP30 Impairs Lung Microvascular Endothelial Integrity Through Deubiquitinating MAT2A in Acute Lung Injury

Abstract Microvascular dysfunction plays a critical role in the pathogenesis of acute lung injury by increasing leakage of plasma fluid and an influx of leukocytes into interstitial tissues, ultimately leading to lung dysfunction. Despite intensive research, the pathogenic mechanisms of microvascular dysfunction are not fully understood. Here, we elucidate that increased activation of USP30 promotes lung microvascular inflammation and endothelial cell (EC) barrier disruption. We find that inhibiting USP30 preserves EC function by modulating S-adenosylmethionine (SAM) cycle, DNA methylation, and miR-30a-5p expression. Mechanistically, deletion of USP30 destabilizes methionine adenosyltransferase 2A (MAT2A), lowers methyl donor SAM levels, and decreases DNA methylation, leading to increase miR-30a-5p expression. MiR-30a-5p diminishes MDM2 and NFAT5 expression, leading to preserve EC integrity. Mice with EC-specific USP30 deficiency show alleviated microvascular dysfunction in endotoxin- and lung ischemia-reperfusion-induced lung injury models. Our results thus implicate there is an undiscovered mechanism by which mitochondrial USP30 modulates EC function. This study suggests that endothelial USP30 is a potential target for treatment of microvascular dysfunction in acute inflammatory diseases. This abstract is funded by: NHLBI