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

Abstract

Genome wide association (GWA) studies have reproducibly identified signals on chromosome 4q24 associated with lung function and COPD. GSTCD (Glutathione S -transferase C-terminal domain containing) represents a candidate causal gene in this locus, however little is currently known about the function of this protein. We set out to further our understanding of the role of GSTCD in cell functions and homeostasis using multiple molecular and cellular approaches in airway relevant cells. Recombinant expression of human GSTCD in conjunction with a GST activity assay did not identify any enzymatic activity for two GSTCD isoforms questioning the assignment of this protein to this family of enzymes. Protein structure analyses identified a potential methyltransferase domain contained within GSTCD, with these enzymes linked to cell viability and apoptosis. Targeted knockdown (siRNA) of GSTCD in bronchial epithelial cells identified a role for GSTCD in cell viability as proliferation rates were not altered. To provide greater insight we completed transcriptomic analyses on cells with GSTCD expression knocked down and identified several differentially expressed genes including those implicated in airway biology; fibrosis e.g. TGFBR1 and inflammation e.g. IL6R . Pathway based transcriptomic analyses identified an over-representation of genes related to adipogenesis which may suggest additional functions for GSTCD. These findings identify potential additional functions for GSTCD in the context of airway biology beyond the hypothesised GST activity and warrant further investigation.

Hidden Glutathione Transferases in the Human Genome

“…While the NTD contains the cis -proline conserved in cGSTs, the G-site appears to be degenerate; superposition of the GSTCD model with cGST/GSH complexes show clashes with GSH (data not shown). Consistent with this is a lack of detectable GST activity [ 40 ]. With the exception of a short helix corresponding to helix α4, the rest of the CTD is rotated approximately 90° with respect to its usual position relative to the NTD.…”

“…GSTCD −/− mice showed an increased lung TNF production in response to lipopolysaccharide. It was predicted to contain a methyltransferase domain [ 40 ].…”

Identification of nine signature proteins involved in periodontitis by integrated analysis of TMT proteomics and transcriptomics

“…GO annotations related to this gene include methyltransferase activity and rRNA methyltransferase activity. GSTCD is closely related to lung function ( 47 ), though there has beenalmost no reports on the relationship between GSTCD and periodontitis to date. In our study, gene expression of GSTCD in gingiva from periodontitis individuals was significantly increased in the GSE10334 (logFC=5.58) and GSE16134 (logFC=5.57) datasets compared with healthy populations, which is consistent with our TMT proteomics results.…”

Integrated Analysis of a circRNA-miRNA-mRNA Axis in Intervertebral Disc Degeneration

“…The hsa_circ_0091570, a sponge of miR-1307 that acted to regulate ISM1 expression in hepatocellular cancer, was screened from the ceRNA network constructed by 8 circRNAs, 13 miRNAs and 15 genes [32]. Three additional genes, CHEK1, TSGA10, and GSTCD, have been reported to downregulate genes that inhibit cellular proliferation or reduce cell numbers [33][34][35]. what's more, NPCs' proliferation and apoptosis play a key role in IDD [36].…”