Acute cigarette smoke exposure impairs proteasome function in the lung

Area of Science:

• Cellular Biology
• Toxicology
• Molecular Biology

Background:

• Cigarette smoke (CS) causes cellular damage through DNA alteration, lipid peroxidation, and protein misfolding.
• The ubiquitin-proteasome system (UPS) is crucial for clearing damaged proteins and maintaining cellular homeostasis.
• The specific role of the UPS in CS-induced cellular damage remains largely uncharacterized.

Purpose of the Study:

• To investigate the involvement of the UPS in the degradation of CS-damaged proteins.
• To determine if CS exposure impairs proteasome function.
• To elucidate the impact of CS on proteasome activity in lung epithelial cells and in vivo.

Main Methods:

• Human alveolar epithelial cells were treated with cigarette smoke extract (CSE).
• Proteasome activity, reactive oxygen species (ROS) levels, and protein ubiquitination were assessed.
• Mice were acutely exposed to CS, and lung proteasome activity was measured.
• Transcriptional regulation of proteasome subunits was analyzed.

Main Results:

• CSE induced time- and dose-dependent cell death, increased ROS, and elevated carbonylated and polyubiquitinated proteins.
• High CSE doses inhibited all proteasomal activities, while low doses selectively inhibited trypsin-like activity in epithelial cells.
• Acute CS exposure in mice reduced lung trypsin-like proteasome activity by 25% without altering proteasome expression.
• CS exposure led to the accumulation of polyubiquitinated proteins in mouse lung.

Conclusions:

• CS directly impairs proteasome activity in lung epithelial cells and in vivo.
• Low-dose CS exposure selectively inhibits trypsin-like proteasome activity.
• Impaired proteasomal protein quality control may contribute to CS-induced lung injury.