title: Nrf-2-driven long noncoding RNA ODRUL contributes to modulating silver nanoparticle-induced effects on erythroid cells.
abstract: The biosafety and biological effects of silver nanoparticles (AgNPs) on human health attract increasing concern. Although considerable studies have been performed to reveal the molecular mechanisms responsible for AgNP-induced effects, the current understanding mainly focuses on oxidative stress-associated signaling pathways activated by Ag particles and/or Ag ions. However, the molecular bases underlying the activation of these stress signaling pathways have not been thoroughly elucidated yet. In the current study, we aimed to shed light on the molecular bases of AgNP-induced effects on erythroid cells from the perspective of long noncoding RNAs. We identified a long-noncoding RNA molecule, ODRUL, which was substantially enhanced in K562 erythroid cells responding to AgNPs, coupled to accelerated cell death. Further, we uncovered oxidative stress-driven Nrf2 transcriptionally promoted ODRUL expression in K562 cells. Downstream of Nrf2-ODRUL activation by AgNPs, ODRUL was recognized to interact with PI4Kα protein to modulate the activities of its targets AKT and JNK. As a result, the Bcl-2 level was negatively regulated by PI4K-AKT/JNK signaling under AgNP-induced stress, leading to enhanced cell death. Together, our findings unearthed that Nrf2-mediated lncRNA ODRUL was indispensable for AgNP-induced toxicity in erythroid cells through regulation of AKT/JNK-Bcl-2 signaling dependent on a physical interaction with PI4Kα. Thus, this study would open a new path to depict the molecular bases of AgNP-induced effects on erythroid cells.
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.affiliation: College of Environmental Science and Engineering, Ministry of Education Key Laboratory of Pollution Processes and Environmental Criteria, Tianjin Key Laboratory of Environmental Remediation and Pollution Control, Nankai University, Tianjin, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Zhao
authors.affiliation: College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, China.
authors.forename: Minjun
authors.initials: M
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences and Anhui Province, Hefei, Anhui 230031, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province 453003, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China. Electronic address: sjliu@rcees.ac.cn.
authors.forename: Sijin
authors.initials: S
authors.lastname: Liu
authors.affiliation: College of Environmental Science and Engineering, Ministry of Education Key Laboratory of Pollution Processes and Environmental Criteria, Tianjin Key Laboratory of Environmental Remediation and Pollution Control, Nankai University, Tianjin, China. Electronic address: zhangchengdong@nankai.edu.cn.
authors.forename: Chengdong
authors.initials: C
authors.lastname: Zhang
mesh_terms: D016923:Cell Death / Q000187:drug effects; D041905:Erythroid Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020014:K562 Cells; D053768:Metal Nanoparticles / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012834:Silver / Q000494:pharmacology*
chemical_list: D015778:Minor Histocompatibility Antigens; D051267:NF-E2-Related Factor 2; D019253:Proto-Oncogene Proteins c-bcl-2; D062085:RNA, Long Noncoding; C000625644:long non-coding RNA ODRUL, human; D012834:Silver; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Cell death; Erythroid cells; ODRUL; Silver nanoparticles; lncRNA