The effect of cysteine oxidation on DJ-1 cytoprotective function in human alveolar type II cells
| Autor: | Karim Bahmed, Hsin Yao Tang, Jiusheng Lin, Tessa Andrews, Samia Boukhenouna, Robert John Mason, Loukmane Karim, Elise M. Messier, Gerard J. Criner, Robert Powers, Mark A. Wilson, Roger Powell, Chih-Ru Lin, Beata Kosmider, Nichole Reisdorph |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cancer Research Protein Deglycase DJ-1 Immunology Mitochondrion Transfection medicine.disease_cause Article 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor medicine Humans Cysteine Propidium iodide lcsh:QH573-671 Cysteine metabolism Aged chemistry.chemical_classification A549 cell Respiratory tract diseases Reactive oxygen species lcsh:Cytology Cell Biology Middle Aged Cell biology Oxidative Stress Mechanisms of disease 030104 developmental biology chemistry Cell culture Alveolar Epithelial Cells 030220 oncology & carcinogenesis Female Oxidation-Reduction Oxidative stress |
| Zdroj: | Cell Death and Disease, Vol 10, Iss 9, Pp 1-14 (2019) Cell Death & Disease |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/s41419-019-1833-5 |
| Popis: | DJ-1 is a multifunctional protein with cytoprotective functions. It is localized in the cytoplasm, nucleus, and mitochondria. The conserved cysteine residue at position 106 (Cys106) within DJ-1 serves as a sensor of redox state and can be oxidized to both the sulfinate (-SO2−) and sulfonate (-SO3−) forms. DJ-1 with Cys106-SO2− has cytoprotective activity but high levels of reactive oxygen species can induce its overoxidation to Cys106-SO3−. We found increased oxidative stress in alveolar type II (ATII) cells isolated from emphysema patients as determined by 4-HNE expression. DJ-1 with Cys106-SO3− was detected in these cells by mass spectrometry analysis. Moreover, ubiquitination of Cys106-SO3− DJ-1 was identified, which suggests that this oxidized isoform is targeted for proteasomal destruction. Furthermore, we performed controlled oxidation using H2O2 in A549 cells with DJ-1 knockout generated using CRISPR-Cas9 strategy. Lack of DJ-1 sensitized cells to apoptosis induced by H2O2 as detected using Annexin V and propidium iodide by flow cytometry analysis. This treatment also decreased both mitochondrial DNA amount and mitochondrial ND1 (NADH dehydrogenase 1, subunit 1) gene expression, as well as increased mitochondrial DNA damage. Consistent with the decreased cytoprotective function of overoxidized DJ-1, recombinant Cys106-SO3− DJ-1 exhibited a loss of its thermal unfolding transition, mild diminution of secondary structure in CD spectroscopy, and an increase in picosecond–nanosecond timescale dynamics as determined using NMR. Altogether, our data indicate that very high oxidative stress in ATII cells in emphysema patients induces DJ-1 overoxidation to the Cys106-SO3− form, leading to increased protein flexibility and loss of its cytoprotective function, which may contribute to this disease pathogenesis. |
| Databáze: | OpenAIRE |
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