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Quantitative reactive cysteinome profiling reveals a functional link between ferroptosis and proteasome-mediated degradation.

ABSTRACT: Ferroptosis is a unique type of cell death that is hallmarked with the imbalanced redox homeostasis as triggered by iron-dependent lipid peroxidation. Cysteines often play critical roles in proteins to help maintain a healthy cellular environment by dynamically switching between their reduced and oxidized forms, however, how the global redox landscape of cysteinome is perturbed upon ferroptosis remains unknown to date. By using a quantitative chemical proteomic strategy, we systematically profiled the dynamic changes of cysteinome in ferroptotic cells and identified a list of candidate sites whose redox states are precisely regulated under ferroptosis-inducing and rescuing conditions. In particular, C106 of the protein/nucleic acid deglycase DJ-1 acts as an intriguing sensor switch for the ferroptotic condition, whose oxidation results in the disruption of its interaction with the 20S proteasome and leads to a marked activation in the proteasome system. Our chemoproteomic profiling and associated functional studies reveal a novel functional link between ferroptosis and the proteasome-mediated protein degradation and suggest proteasome as a promising target for developing treatment strategies for ferroptosis-related diseases.

ORGANISM(S): Homo Sapiens

SUBMITTER: Chu Wang

PROVIDER: PXD029874 | iProX | Tue Nov 23 00:00:00 GMT 2021

REPOSITORIES: iProX

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Quantitative reactive cysteinome profiling reveals a functional link between ferroptosis and proteasome-mediated degradation.

Wang Yankun Y Wang Chu C

Cell death and differentiation 20220816 1

Ferroptosis is a unique type of cell death that is hallmarked with the imbalanced redox homeostasis as triggered by iron-dependent lipid peroxidation. Cysteines often play critical roles in proteins to help maintain a healthy cellular environment by dynamically switching between their reduced and oxidized forms, however, how the global redox landscape of cysteinome is perturbed upon ferroptosis remains unknown to date. By using a quantitative chemical proteomic strategy, we systematically profil ...[more]

PMID: 35974250

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Project description:Alzheimer’s disease (AD), currently affecting millions of people worldwide, is the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. Here we evaluate if Aβ is associated with ferroptosis pathways and whether ferroptosis inhibition could attenuate Aβ-related effects. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Performing positive pixel density scoring on immunohistochemically stained post mortem BA17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 (NCOA4) and glutathione peroxidase 4 (GPX4) in the grey matter (GM). The expression of ferroportin, NCOA4, GPX4, 4-hydroxy-2-nonenal (4HNE) and cytochrome C was significantly lower, while the expression of ferritin was higher in the Aβ plaque area compared to the immediate vicinity of the non-Aβ tissue in AD brain tissue. Taken together, these findings indicate a relationship between Aβ-related processes and the expression of ferroptosis-related proteins. Additionally, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids (cBOs). Differential expression analysis of AD organoids compared to isogenic controls indicate activation of the ferroptotic pathway. This further supports the previously suggested link between Aβ-related pathology and ferroptosis. Determining the causality between development of Aβ plaques and deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions.

Project description:Ferroptosis is a form of regulated cell death driven by lipid peroxidation of polyunsaturated fatty acids (PUFAs). Endogenous PUFAs are nonconjugated PUFAs and their peroxidation proceeds via the hydrogen-atom transfer (HAT) mechanism. We previously reported that lipids with conjugated double bonds undergo lipid peroxidation mostly via a different mechanism, peroxyl radical addition (PRA), and were much more readily oxidizable than nonconjugated ones. In this study, we aim to elucidate the effects of various unsaturated lipids in sensitizing ferroptosis. We found that while some peroxidation-reactive lipids, such as 7-dehydrocholesterol, vitamins D3 and A, and coenzyme Q10, suppress ferroptosis, both nonconjugated and conjugated PUFAs enhanced cell death induced by RSL3, a ferroptosis inducer. Importantly, we showed that conjugated linolenic acid (CLA 18:3) could act as a ferroptosis inducer by itself and conjugated linoleic acid (CLA 18:2) was more potent in sensitizing cells to RSL3-induced cell death than any nonconjugated PUFAs. We next sought to elucidate the mechanism underlying the different ferroptosis-inducing potency of conjugated and nonconjugated PUFAs. Lipidomics revealed that conjugated and nonconjugated PUFAs are incorporated into distinct cellular lipid species. Furthermore, the different peroxidation mechanisms predict the formation of higher levels of reactive electrophilic aldehydes from conjugated PUFAs than nonconjugated PUFAs, which was confirmed by aldehyde-trapping and mass spectrometry. RNA sequencing revealed that protein processing in the endoplasmic reticulum and proteasome are among the most significantly upregulated pathways in cells treated with CLA 18:3, suggesting increased ER stress and activation of unfolded protein response. Significantly, using click chemistry, we observed increased protein adduction by oxidized lipids in cells treated with an alkynylated CLA 18:2 probe. These results suggest that protein damage by lipid electrophiles is a key step in ferroptosis.

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Quantitative reactive cysteinome profiling reveals a functional link between ferroptosis and proteasome-mediated degradation.

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Quantitative reactive cysteinome profiling reveals a functional link between ferroptosis and proteasome-mediated degradation.

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