title: TP53-dependent autophagy links the ATR-CHEK1 axis activation to proinflammatory VEGFA production in human bronchial epithelial cells exposed to fine particulate matter (PM2.5).
abstract: ABSTARCT Epidemiological and clinical studies have increasingly shown that fine particulate matter (PM2.5) is associated with a number of pathological respiratory diseases, such as bronchitis, asthma, and chronic obstructive pulmonary disease, which share the common feature of airway inflammation induced by particle exposure. Thus, understanding how PM2.5 triggers inflammatory responses in the respiratory system is crucial for the study of PM2.5 toxicity. In the current study, we found that exposing human bronchial epithelial cells (immortalized Beas-2B cells and primary cells) to PM2.5 collected in the winter in Wuhan, a city in southern China, induced a significant upregulation of VEGFA (vascular endothelial growth factor A) production, a signaling event that typically functions to control chronic airway inflammation and vascular remodeling. Further investigations showed that macroautophagy/autophagy was induced upon PM2.5 exposure and then mediated VEGFA upregulation by activating the SRC (SRC proto-oncogene, non-receptor tyrosine kinase)-STAT3 (signal transducer and activator of transcription 3) pathway in bronchial epithelial cells. By exploring the upstream signaling events responsible for autophagy induction, we revealed a requirement for TP53 (tumor protein p53) activation and the expression of its downstream target DRAM1 (DNA damage regulated autophagy modulator 1) for the induction of autophagy. These results thus extend the role of TP53-DRAM1-dependent autophagy beyond cell fate determination under genotoxic stress and to the control of proinflammatory cytokine production. Moreover, PM2.5 exposure strongly induced the activation of the ATR (ATR serine/threonine kinase)-CHEK1/CHK1 (checkpoint kinase 1) axis, which subsequently triggered TP53-dependent autophagy and VEGFA production in Beas-2B cells. Therefore, these findings suggest a novel link between processes regulating genomic integrity and airway inflammation via autophagy induction in bronchial epithelial cells under PM2.5 exposure.
authors.affiliation: a Department of Stress Medicine , Beijing Institute of Basic Medical Sciences , Beijing , China.|b Anhui Medical University , Hefei , China.
authors.forename: Xiuduan
authors.initials: X
authors.lastname: Xu
authors.affiliation: a Department of Stress Medicine , Beijing Institute of Basic Medical Sciences , Beijing , China.|c Laboratory of Cellular and Molecular Immunology, School of Medicine, Henan University , Kaifeng , China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Wang
authors.affiliation: a Department of Stress Medicine , Beijing Institute of Basic Medical Sciences , Beijing , China.|d Department of Pathology , School of Basic Medical Sciences, Lanzhou University , Lanzhou , China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Liu
authors.affiliation: a Department of Stress Medicine , Beijing Institute of Basic Medical Sciences , Beijing , China.
authors.forename: Chen
authors.initials: C
authors.lastname: Xing
authors.affiliation: e Department of Thoracic Surgery, Chinese PLA General Hospital , Beijing , China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: a Department of Stress Medicine , Beijing Institute of Basic Medical Sciences , Beijing , China.|f Department of New Drug Screening Center , China Pharmaceutical University , Nanjing , China.
authors.lastname: Aodengqimuge
authors.affiliation: g Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention , Beijing , China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: g Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention , Beijing , China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yuan
authors.affiliation: e Department of Thoracic Surgery, Chinese PLA General Hospital , Beijing , China.
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Ma
authors.affiliation: a Department of Stress Medicine , Beijing Institute of Basic Medical Sciences , Beijing , China.
authors.forename: Meiru
authors.initials: M
authors.lastname: Hu
authors.affiliation: a Department of Stress Medicine , Beijing Institute of Basic Medical Sciences , Beijing , China.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: a Department of Stress Medicine , Beijing Institute of Basic Medical Sciences , Beijing , China.
authors.forename: Shuxian
authors.initials: S
authors.lastname: Zou
authors.affiliation: a Department of Stress Medicine , Beijing Institute of Basic Medical Sciences , Beijing , China.|d Department of Pathology , School of Basic Medical Sciences, Lanzhou University , Lanzhou , China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Gu
authors.affiliation: g Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention , Beijing , China.
authors.forename: Shuangqing
authors.initials: S
authors.lastname: Peng
authors.affiliation: f Department of New Drug Screening Center , China Pharmaceutical University , Nanjing , China.
authors.forename: Shengtao
authors.initials: S
authors.lastname: Yuan
authors.affiliation: d Department of Pathology , School of Basic Medical Sciences, Lanzhou University , Lanzhou , China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Li
authors.affiliation: c Laboratory of Cellular and Molecular Immunology, School of Medicine, Henan University , Kaifeng , China.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: a Department of Stress Medicine , Beijing Institute of Basic Medical Sciences , Beijing , China.|b Anhui Medical University , Hefei , China.
authors.forename: Lun
authors.initials: L
authors.lastname: Song
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001343:Autophagy; D001980:Bronchi / Q000473:pathology*; D000071877:Checkpoint Kinase 1 / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D052638:Particulate Matter / Q000009:adverse effects*; D000090063:Proto-Oncogene Mas; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C000715470:MAS1 protein, human; D052638:Particulate Matter; D000090063:Proto-Oncogene Mas; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019061:src-Family Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1
keywords: PM2.5; TP53; VEGFA; autophagy; inflammation