USP13 deficiency aggravates cigarette smoke-induced alveolar space enlargement through stabilization of TXNIP.

Deubiquitinating enzymes regulate cellular function through deubiquitination and stabilization of substrate proteins. We have shown that USP13 deficiency promotes lung inflammation. Cigarette smoke (CS) causes lung connective tissue disruption and oxidative stress in lung cells, resulting in the development of emphysema; however, the role of USP13 in the CS exposure-induced emphysema has not been well studied. USP13-deficient mice and wild type mice were exposed to 4 unfiltered cigarettes for 5 days each week, over the course of 6 months. While emphysema was not observed in wild type mice, CS exposure increased γ-H2AX levels in lung tissues, suggesting a model of mild smoke exposure was established. Under the mild CS exposure condition, USP13-deficient mice show significant increases in alveolar CL, indicating that USP13-deficient mice are susceptible to CS-induced alveolar enlargement. We have shown that USP13 knockout reduced fibronectin expression in lungs. Further, we found that collagen levels were reduced in USP13-siRNA-transfected lung fibroblast cells. It is possible that a loss of connective tissue function contributes to alveolar enlargement in USP13-deficient mice. Oxidative stress is a hallmark of CS-induced emphysema. We investigated the role of USP13 in the expression of an oxidative stress markers, named thioredoxin interacting protein (TXNIP), which modulates cellular redox states and NLRP3 inflammasome activity. TXNIP expression levels have been shown to be decreased in smokers compared with non-smokers. TXNIP is unstable in the presence of protein synthesis inhibitor cycloheximide (CHX). Pretreatment with proteasome inhibitor, MG-132, attenuated TXNIP degradation, suggesting that TXNIP degradation is mediated by the proteasome. Knockout or knockdown of USP13 in lungs or lung fibroblast cells significantly reduced TXNIP levels. TXNIP degradation is increased in USP13 knockdown cells. Further, the reduction of TXNIP was observed in USP13-inhibitor-treated mouse lung epithelial cells. This study provides evidence showing that USP13 deficiency plays a role in alveolar space enlargement.