Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease

Kingsford-Adaboh, Robert; Zhu, Max; Jójárt, Balázs; Czajlik, András; Solti, Katalin; Fórizs, Balázs; Nagy, Éva; Zsila, Ferenc; Beke‐Somfai, Tamás; Tóth, Gergely

doi:10.1016/j.bbagen.2017.08.017

Cited by 40 publications

(42 citation statements)

References 60 publications

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“…Additionally, the cytoprotective interaction of DJ-1 with apoptosis signal-regulating kinase 1 (ASK1) was mediated by SO 2 H and modulated by peripheral C46 and C53 (29,30). However, high oxidation of C106 to SO 3 H results in aggregated and inactive DJ-1, and has been correlated with the increased progression of disease including PD where oxidative stress is a part of the pathophysiology (27,31).…”

Section: The Multifaceted Roles Of Dj-1 As An Antioxidantmentioning

confidence: 99%

Role of DJ-1 in Immune and Inflammatory Diseases

Zhang

Wang

et al. 2020

Front. Immunol.

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The DJ-1 protein, known as an oxidative stress sensor, participates in the onset of oxidative stress-related diseases such as cancer, neurodegenerative disorders, type 2 diabetes, and male infertility. Although DJ-1 has been extensively studied for more than two decades, evidence has only recently emerged that it plays a key role in immune and inflammatory disorders. The immune regulatory function of DJ-1 is achieved by modulating the activation of several immune cells including macrophages, mast cells, and T cells via reactive oxygen species (ROS)-dependent and/or ROS-independent mechanisms. This review describes the current knowledge on DJ-1, focusing on its immune and inflammatory regulatory roles, and highlights the significance of DJ-1 as a novel therapeutic target for immune and inflammatory diseases.

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Section: The Multifaceted Roles Of Dj-1 As An Antioxidantmentioning

confidence: 99%

Role of DJ-1 in Immune and Inflammatory Diseases

Zhang

Wang

et al. 2020

Front. Immunol.

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“…Canet-Aviles et al observed that cysteine-sulfinic acid formation in DJ-1 is necessary for mitochondrial targeting and neuroprotection [ 307 ], and consistent with this, Zhou et al demonstrated that the sulfinic DJ-1 isoform prevents α -synuclein fibrillation [ 308 ]. Conversely, in the presence of high levels of oxidative stress, DJ-1 is oxidised to the sulfonic form; this isoform is inactive and predisposed to aggregate formation, and indeed, this overoxidised isoform has been detected in brains from Parkinson's patients [ 309 , 310 ]. In addition, Ozawa et al highlighted the crucial role of DJ-1 in the nitrosylation of Parkin, and suggested that DJ-1 inactivation reduces mitophagy, leading to mitochondrial dysfunction and Parkinson's pathogenesis [ 311 ].…”

Section: Autophagy and Redoxtasis Crosstalkmentioning

confidence: 99%

Autophagy and Redox Homeostasis in Parkinson’s: A Crucial Balancing Act

Jiménez-Moreno

Lane

2020

Oxidative Medicine and Cellular Longevity

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Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated primarily from endogenous biochemical reactions in mitochondria, endoplasmic reticulum (ER), and peroxisomes. Typically, ROS/RNS correlate with oxidative damage and cell death; however, free radicals are also crucial for normal cellular functions, including supporting neuronal homeostasis. ROS/RNS levels influence and are influenced by antioxidant systems, including the catabolic autophagy pathways. Autophagy is an intracellular lysosomal degradation process by which invasive, damaged, or redundant cytoplasmic components, including microorganisms and defunct organelles, are removed to maintain cellular homeostasis. This process is particularly important in neurons that are required to cope with prolonged and sustained operational stress. Consequently, autophagy is a primary line of protection against neurodegenerative diseases. Parkinson’s is caused by the loss of midbrain dopaminergic neurons (mDANs), resulting in progressive disruption of the nigrostriatal pathway, leading to motor, behavioural, and cognitive impairments. Mitochondrial dysfunction, with associated increases in oxidative stress, and declining proteostasis control, are key contributors during mDAN demise in Parkinson’s. In this review, we analyse the crosstalk between autophagy and redoxtasis, including the molecular mechanisms involved and the detrimental effect of an imbalance in the pathogenesis of Parkinson’s.

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“…This irreversible form has been suggested to inactivate DJ-1 function 22–24 ; however, the mechanism is not well understood. Accumulation of Cys106-SO 3 − DJ-1 has been correlated to diseases development where oxidative stress is a part of pathophysiology 25 . We have recently reported the cytoprotective role of DJ-1 against ATII cell injury in smokers 26 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease

Cited by 40 publications

References 60 publications

Role of DJ-1 in Immune and Inflammatory Diseases

Role of DJ-1 in Immune and Inflammatory Diseases

Autophagy and Redox Homeostasis in Parkinson’s: A Crucial Balancing Act

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

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