Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0034067 (
emphysema
)
11,506
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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 (-SO
2
-
) and sulfonate (-SO
3
-
) forms. DJ-1 with Cys106-SO
2
-
has cytoprotective activity but high levels of reactive oxygen species can induce its overoxidation to Cys106-SO
3
-
. 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-SO
3
-
was detected in these cells by mass spectrometry analysis. Moreover, ubiquitination of Cys106-SO
3
-
DJ-1 was identified, which suggests that this oxidized isoform is targeted for proteasomal destruction. Furthermore, we performed controlled oxidation using H
2
O
2
in A549 cells with DJ-1 knockout generated using CRISPR-Cas9 strategy. Lack of DJ-1 sensitized cells to apoptosis induced by H
2
O
2
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-SO
3
-
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-SO
3
-
form, leading to increased protein flexibility and loss of its cytoprotective function, which may contribute to this disease pathogenesis.
...
PMID:The effect of cysteine oxidation on DJ-1 cytoprotective function in human alveolar type II cells. 3147 49
