FK506-binding protein 13 expression is upregulated in interstitial lung disease and correlated with clinical severity: a potentially protective role

Abstract

23Pulmonary fibrosis is a progressive lung disease characterized by myofibroblast accumulation and 24 excessive extracellular matrix deposition. Endoplasmic reticulum (ER) stress initiates the unfolded 25 protein response (UPR), a cellular stress response pathway that has been implicated in both 26 inflammatory and fibrotic processes. Here, we sought to investigate the role of the 13 kDa FK506-27 binding protein (FKBP13), an ER stress-inducible molecular chaperone, in various forms of pulmonary 28 fibrosis. We first characterized the gene and protein expression of FKBP13 in lung biopsy samples 29 from 24 patients with idiopathic pulmonary fibrosis (IPF) and 17 control subjects. FKBP13 expression 30 was found to be elevated in the fibrotic regions of IPF lung tissues, and within this cohort, was 31 correlated with declining forced vital capacity and dyspnea severity. FKBP13 expression was also 32 increased in lung biopsies of patients with hypersensitivity pneumonitis, rheumatoid arthritis, and 33 sarcoidosis-associated interstitial lung disease. We next evaluated the role of this protein using 34 FKBP13 -/mice in a bleomycin model of pulmonary fibrosis. Animals were assessed for lung function 35 and histopathology at different stages of lung injury including the inflammatory (Day 7), fibrotic (Day 36 21) and resolution (Day 50) phase. FKBP13 -/mice showed increased infiltration of inflammatory cells 37 and cytokines at Day 7, increased lung elastance and fibrosis at Day 21, and impaired resolution of 38 fibrosis at Day 50. These changes were associated with an increased number of cells that stained 39 positive for TUNEL and cleaved caspase 3 in the FKBP13 -/lungs, indicating a heightened cellular 40 sensitivity to bleomycin. Our findings suggest that FKBP13 is a potential biomarker for severity or 41 progression of interstitial lung diseases, and that it has a biologically relevant role in protecting mice 42 against bleomycin-induced injury, inflammation and fibrosis. 43 following the description provided by Reyfman et al. (2018) [19] using Seurat [20] package in R. t-131 distributed stochastic neighbor embedding (tSNE plot), expression plot and violin plots were created 132 using Seurat package. Cell populations were defined by using the genes reported to be differentially 133 expressed between the cell populations [19]. 134 Animal Experiments: All animal work was approved by the Animal Research Ethics Board of 135 McMaster University (Hamilton, ON, Canada) under protocol number 12.02.06. Male C57BL6/J mice 136 aged 10-12 weeks were bred and housed at the McMaster University Central Animal Facility (CAF, 137Hamilton, ON, Canada). Animals were kept on a 12-hour light/dark cycle at a controlled temperature of 138 20-25°C and ambient humidity of ~50%. The animals were allowed access to food and water and were 139 fed ad libitum. 140

Monocyte and macrophage derived myofibroblasts: Is it fate? A review of the current evidence

“…Work completed using human lung tissues was as previously described. 60 In short, procedures using human tissues were approved by the Hamilton Integrated Research Ethics Board (11-3559 and 13-523-C). FFPE IPF lung tissue samples were acquired from the biobank for lung diseases at St. Joseph's Hospital in Hamilton, Ontario, and selected based on the evaluation of trained molecular pathologists and radiologists.…”

FK506-binding protein 2 (FKBP13) inhibit Bax-induced apoptosis in Saccharomyces cerevisiae (yeast)

“…FKPB13 is an endoplasmic reticulum (ER) chaperone (Tat et al 2021); the FKBP2 gene encodes FKBP13 (Boon et al 2009); its molecular function includes transport between trans-proline and cis-proline residues for appropriate folding of the protein in the lumen of the ER (Jeong et al 2017). FKBP13 has been reported to be upregulated through ER stress (Bush et al 1995) which is believed to be vital for the maintenance of ER protein homeostasis as part of the unfolded protein response (Jeong et al 2017).…”

FKBP13: A New Player on the Block in Endoplasmic Reticulum Stress and Lung Fibrosis

“…Do all ER chaperones play roles in lung fibrosis and interstitial lung disease, as does GRP78? Here, Tat and colleagues provide some mechanistic insight into another ER chaperone in lung fibrosis, the 13-kD FK506-binding protein (FKBP13) (7). Previous studies have reported finding increased expression of the FKBP2 gene (which encodes FKBP13) in fibrotic lungs and a correlation of expression levels with disease progression of lung fibrosis (8) and chronic hypersensitivity pneumonitis (9).…”