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USP13 Deficiency Aggravates Cigarette-smoke-induced Alveolar Space Enlargement.
Cell Biochemistry and Biophysics  (IF2.194),  Pub Date : 2021-05-25, DOI: 10.1007/s12013-021-01000-0
Alyssa D Gregory,Kevin C Tran,Arya S Tamaskar,Jianxin Wei,Jing Zhao,Yutong Zhao

Alveolar enlargement is a pathological feature of emphysema. Long-term exposure to cigarette smoke (CS) is a high-risk factor for the development of emphysema. Abnormal protein ubiquitination has been implicated to regulate the development of human disorders, however, the role of protein ubiquitination in emphysema has not been well-studied. In this study, we attempted to investigate if a deubiquitinase, USP13, regulates the development of emphysema. Under a mild CS exposure condition, USP13-deficient mice show significant increases in alveolar chord length, indicating that USP13-deficient mice are susceptible to CS-induced alveolar enlargement. It has been shown that USP13 knockout reduced fibronectin expression in lungs. Here, we found that collagen levels were reduced in USP13 siRNA-transfected lung fibroblast cells. This suggests that a loss of extracellular matrix in connective tissues contributes to alveolar enlargement in USP13-deficient mice in response to CS exposure. Further, we investigated the role of USP13 in the expression of oxidative stress markers TXNIP and HMOX1. An increase in HMOX1 abundance was observed in USP13 knockdown lung fibroblast and epithelial cells. Overexpression of USP13 reduced HMOX1 protein levels in lung fibroblast cells, suggesting that modulation of USP13 levels may affect oxidative stress. Knockdown of USP13 significantly reduced TXNIP levels in lungs or lung fibroblast cells. A protein stability pulse-chase assay showed that TXNIP is instable within USP13 knockdown lung fibroblast cells. Further, the reduction of TXNIP was observed in USP13 inhibitor-treated lung epithelial cells. USP13-deficient mice also show higher levels of IgG in bronchoalveolar lavage fluid. This study provides evidence showing that USP13 deficiency plays a role in alveolar space enlargement.