USP19 protects against cigarette smoke-induced lung injury and epithelial stress.

Cigarette smoke (CS) imposes substantial proteostatic stress on lung epithelial cells, yet the protein quality control mechanisms that determine susceptibility to injury remain incompletely understood. We investigated the role of the ubiquitin-specific protease 19 (USP19) in CS-related lung injury across human lung tissue, a chronic CS-exposure mouse model, and cigarette smoke extract (CSE)-treated bronchial epithelial BEAS-2B cells. USP19 protein abundance was reduced in lung tissue from patients with severe COPD. Usp19-deficient mice developed greater CS-induced airspace enlargement compared to wild-type mice. In BEAS-2B cells, CSE reduced USP19 abundance, and USP19 knockout increased CSE-induced apoptosis. In addition, re-expression of USP19 partially restored viability. USP19 deficiency altered the temporal profile of integrated stress response signaling, culminating in enhanced CHOP induction, and CHOP (DDIT3) knockdown partially rescued CSE-induced loss of viability. USP19-deficient cells also showed a decrease in p62 abundance, puncta number, and area during CSE exposure, suggesting altered p62-associated protein handling. Together, these findings identify USP19 as a protective modifier of CS-related lung injury and epithelial stress, consistent with a role in supporting the capacity of lung epithelial cells to accommodate CS-induced proteostatic stress.