The effect of cysteine oxidation on DJ-1 cytoprotective function in human alveolar type II cells

Karim Bahmed, Samia Boukhenouna, Loukmane Karim, Tessa Andrews, Jiusheng Lin, Robert Powers, Mark A. Wilson, Chih Ru Lin, Elise Messier, Nichole Reisdorph, Roger L. Powell, Hsin Yao Tang, Robert J. Mason, Gerard J. Criner, Beata Kosmider

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number638
JournalCell Death and Disease
Volume10
Issue number9
DOIs
StatePublished - Sep 1 2019

    Fingerprint

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Bahmed, K., Boukhenouna, S., Karim, L., Andrews, T., Lin, J., Powers, R., Wilson, M. A., Lin, C. R., Messier, E., Reisdorph, N., Powell, R. L., Tang, H. Y., Mason, R. J., Criner, G. J., & Kosmider, B. (2019). The effect of cysteine oxidation on DJ-1 cytoprotective function in human alveolar type II cells. Cell Death and Disease, 10(9), [638]. https://doi.org/10.1038/s41419-019-1833-5