Club cell-specific role of programmed cell death 5 in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) causes progressive fibrosis and worsening pulmonary function. Prognosis is poor and no effective therapies exist. We show that programmed cell death 5 (PDCD5) expression is increased in the lungs of patients with IPF and in mouse models of lung fibrosis. Lung fibrosis is significantly diminished by club cell-specific deletion of Pdcd5 gene. PDCD5 mediates β-catenin/Smad3 complex formation, promoting TGF-β-induced transcriptional activation of matricellular genes. Club cell Pdcd5 knockdown reduces matricellular protein secretion, inhibiting fibroblast proliferation and collagen synthesis. Here, we demonstrate the club cell-specific role of PDCD5 as a mediator of lung fibrosis and potential therapeutic target for IPF.

Bifurcation and Potential Landscape of p53 Dynamics Depending on PDCD5 Level and ATM Degradation Rate

The dynamic behavior of the tumor suppressor p53 as an important signal in response to various stresses can influence cellular fate decisions. Programmed cell death 5 (PDCD5) and wild type p53-induced phosphatase 1 (Wip1) regulate p53 dynamics as its activator and inhibitor, respectively. In the present study, we add Wip1 to p53-Mdm2 (Murine double minute 2) module with PDCD5 and focus on p53 dynamics depending on PDCD5 and ataxia telangiectasia mutated (ATM) degradation rate regulated by Wip1. The bifurcation results reveal that p53 dynamics varies with these two parameters. p53 exhibits monostability and bistabiltiy for smaller and larger PDCD5 level while p53 shows oscillation or coexistence of oscillation and steady states in a narrow parameter range. These dynamics are further explored by time series and potential landscapes. Our results may be useful for regulating cell fate upon DNA damage.

Effect of Tiotropium Bromide on Airway Inflammation and Programmed Cell Death 5 in a Mouse Model of Ovalbumin-Induced Allergic Asthma

Rationale. We previously demonstrated increased expression of programmed cell death 5 (PDCD5) in asthmatic patients and ovalbumin-induced allergic asthma. International guidelines (GINA 2019) have included the use of tiotropium bromide for chronic treatment of the most severe and frequently exacerbated asthma in patients ≥6 years old, who do not have good response to inhaled corticosteroids. Objective. To explore the role of tiotropium and its effect on PDCD5 level in a mouse model of chronic asthma. Methods. We divided 12 female mice into 2 groups: untreated asthma (n = 6) and tiotropium-treated asthma (n = 6). The impact of tiotropium was assessed by histology of lung tissue and morphometry. Pulmonary function was tested by using pressure sensors. The number of cells in bronchoalveolar lavage fluid (BALF) was detected. Levels of PDCD5, active caspase-3, and muscarinic acetylcholine receptors M2 (ChRM2) and M3 (ChRM3) were examined. Results. Tiotropium treatment significantly reduced airway inflammation and remodeling in asthmatic mice and intensified the lung function. PDCD5 level was reduced with tiotropium (p<0.05). Moreover, active caspase-3 level was decreased with tiotropium (p<0.001), and ChRM3 level was increased. Conclusions. Tiotropium treatment may alleviate the pathological changes with asthma by regulating apoptosis.

Crystal structure of the programmed cell death 5 protein from Sulfolobus solfataricus

Programmed cell death 5 (PDCD5) is a vital signaling protein in the apoptosis pathway in eukaryotes. It is known that there are two dissociated N-terminal regions and a triple-helix core in eukaryotic PDCD5. Structural and functional studies of PDCD5 from hyperthermophilic archaea have been limited to date. Here, the PDCD5 homolog Sso0352 (SsoPDCD5) was identified in Sulfolobus solfataricus, the SsoPDCD5 protein was expressed and crystallized, and the phase was identified by single-wavelength anomalous diffraction. The native SsoPDCD5 crystal belonged to space group C2 and diffracted to 1.49 Å resolution. This is the first crystal structure of a PDCD5 homolog to be solved. SsoPDCD5 shares a similar triple-helix bundle with eukaryotic PDCD5 but has a long α-helix in the N-terminus. A structural search and biochemical data suggest that SsoPDCD5 may function as a DNA-binding protein.

Programmed cell death 5 suppresses AKT-mediated cytoprotection of endothelium

Programmed cell death 5 (PDCD5) has been associated with human cancers as a regulator of cell death; however, the role of PDCD5 in the endothelium has not been revealed. Thus, we investigated whether PDCD5 regulates protein kinase B (PKB/AKT)-endothelial nitric oxide synthase (eNOS)–dependent signal transduction in the endothelium and affects atherosclerosis. Endothelial-specific PDCD5 knockout mice showed significantly reduced vascular remodeling compared with wild-type (WT) mice after partial carotid ligation. WT PDCD5 competitively inhibited interaction between histone deacetylase 3 (HDAC3) and AKT, but PDCD5L6R, an HDAC3-binding–deficient mutant, did not. Knockdown of PDCD5 accelerated HDAC3–AKT interaction, AKT and eNOS phosphorylation, and nitric oxide (NO) production in human umbilical vein endothelial cells. Moreover, we found that serum PDCD5 levels reflect endothelial NO production and are correlated with diabetes mellitus, high-density lipoprotein cholesterol, and coronary calcium in human samples obtained from the cardiovascular high-risk cohort. Therefore, we conclude that PDCD5 is associated with endothelial dysfunction and may be a novel therapeutic target in atherosclerosis.