ABSTRACT
Determining the mechanism of senescence-associated pulmonary fibrosis is crucial for designing more effective treatments for chronic lung diseases. This study aimed to determine the following: whether Sirt1 and serum vitamin D decreased with physiological aging, promoting senescence-associated pulmonary fibrosis by activating TGF-ß1/IL-11/MEK/ERK signaling, whether Sirt1 overexpression prevented TGF-ß1/IL-11/MEK/ERK signaling-mediated senescence-associated pulmonary fibrosis in vitamin D-deficient (Cyp27b1-/- ) mice, and whether Sirt1 downregulated IL-11 expression transcribed by TGF-ß1/Smad2 signaling through deacetylating histone at the IL-11 promoter in pulmonary fibroblasts. Bioinformatics analysis with RNA sequencing data from pulmonary fibroblasts of physiologically aged mice was conducted for correlation analysis. Lungs from young and physiologically aged wild-type (WT) mice were examined for cell senescence, fibrosis markers, and TGF-ß1/IL-11/MEK/ERK signaling proteins, and 1,25(OH)2 D3 and IL-11 levels were detected in serum. Nine-week-old WT, Sirt1 mesenchymal transgene (Sirt1Tg ), Cyp27b1-/- , and Sirt1Tg Cyp27b1-/- mice were observed the pulmonary function, aging, and senescence-associated secretory phenotype and TGF-ß1/IL-11/MEK/ERK signaling. We found that pulmonary Sirt1 and serum vitamin D decreased with physiological aging, activating TGF-ß1/IL-11/MEK/ERK signaling, and promoting senescence-associated pulmonary fibrosis. Sirt1 overexpression improved pulmonary dysfunction, aging, DNA damage, senescence-associated secretory phenotype, and fibrosis through downregulating TGF-ß1/IL-11/MEK/ERK signaling in Cyp27b1-/- mice. Sirt1 negatively regulated IL-11 expression through deacetylating H3K9/14ac mainly at the region from -871 to -724 of IL-11 promoter, also the major binding region of Smad2 which regulated IL-11 expression at the transcriptional level, and subsequently inhibiting TGF-ß1/IL-11/MEK/ERK signaling in pulmonary fibroblasts. This signaling in aging fibroblasts could be a therapeutic target for preventing senescence-associated pulmonary fibrosis induced by vitamin D deficiency.
Subject(s)
Interleukin-11/metabolism , Pulmonary Fibrosis , Sirtuin 1/metabolism , Vitamin D Deficiency , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase , Animals , Fibrosis , Mice , Mitogen-Activated Protein Kinase Kinases/adverse effects , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/genetics , Sirtuin 1/genetics , Transforming Growth Factor beta1/metabolism , Vitamin D , Vitamin D Deficiency/complications , Vitamin D Deficiency/geneticsABSTRACT
The COVID-19 pandemic has been a major public health event since 2020. Multiple variant strains of SARS-CoV-2, the causative agent of COVID-19, were detected based on the mutation sites in their sequences. These sequence mutations may lead to changes in the protein structures and affect the binding states of SARS-CoV-2 and human proteins. Experimental research on SARS-CoV-2 has accumulated a large amount of structural data and protein-protein interactions (PPIs), but the studies on the SARS-CoV-2-human PPI networks lack integration of physical associations with possible protein docking information. In addition, the docking structures of variant viral proteins with human receptor proteins are still insufficient. This study constructed SARS-CoV-2-human protein-protein interaction network with data integration methods. Crystal structures were collected to map the interaction pairs. The pairs of direct interactions and physical associations were selected and analyzed for variant docking calculations. The study examined the structures of spike (S) glycoprotein of variants Delta B.1.617.2, Omicron BA.1, and Omicron BA.2. The calculated docking structures of S proteins and potential human receptors were obtained. The study integrated binary protein interactions with 3D docking structures to fulfill an extended view of SARS-CoV-2 proteins from a macro- to micro-scale.