Defining a role for lung function associated gene GSTCD in cell homeostasis

Area of Science:

• Genetics and Molecular Biology
• Cellular Biology
• Respiratory Medicine

Background:

• Genome-wide association studies link chromosome 4q24 to lung function and COPD.
• Glutathione S-transferase C-terminal domain containing (GSTCD) is a candidate gene at this locus, but its function is largely unknown.
• Understanding GSTCD's role is crucial for respiratory disease research.

Purpose of the Study:

• To investigate the cellular functions and homeostasis of the GSTCD protein in airway-relevant cells.
• To explore potential enzymatic activities and structural domains of GSTCD.
• To elucidate GSTCD's role in cell viability and gene expression.

Main Methods:

• Recombinant expression of human GSTCD and GST activity assays.
• Protein structure analysis to identify functional domains.
• siRNA-mediated knockdown of GSTCD in bronchial epithelial cells.
• Transcriptomic analysis (RNA sequencing) to identify differentially expressed genes and pathways.

Main Results:

• GSTCD isoforms showed no detectable glutathione S-transferase (GST) enzymatic activity.
• Protein structure analysis suggested a potential methyltransferase domain.
• GSTCD knockdown affected cell viability but not proliferation rates.
• Transcriptomic analysis revealed differential expression of genes involved in fibrosis (e.g., TGFBR1) and inflammation (e.g., IL6R).
• Pathway analysis indicated an over-representation of adipogenesis-related genes.

Conclusions:

• GSTCD may not function as a typical GST enzyme.
• GSTCD plays a role in cell viability and influences gene expression related to airway biology, including fibrosis and inflammation.
• GSTCD might have functions beyond hypothesized GST activity, potentially involving adipogenesis, warranting further investigation in the context of respiratory diseases.