E3 ligase adaptor FBXO7 contributes to ubiquitination and proteasomal degradation of SIRT7 and promotes cell death in response to hydrogen peroxide

Lee, Su Hyoun; Lee, Yun Ju; Jung, Sungyeon; Chung, Kwang Chul

doi:10.1016/j.jbc.2023.102909

Cited by 8 publications

(10 citation statements)

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“…Numerous substrates of FBXO7 have been reported to date. We recently found that FBXO7 promotes the degradation of FOXO4 and SIRT7 [ 10 , 11 ]. Previous studies further showed that the functional activities of both FOXO4 and SIRT7 are negatively regulated by USP7, without an influence on their stability [ 23 , 24 ].…”

Section: Resultsmentioning

confidence: 99%

“…FBXO7 exerts both protective and toxic effects. For example, we previously reported that FBXO7 triggers neuronal cell death in response to oxidative stress through degradation of cytoprotective FOXO4 and SIRT7 [ 10 , 11 ]. Moreover, FBXO7 promotes the ubiquitination and proteasomal degradation of cytoprotective PINK1 in BEAS-B2 cells [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

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USP7 attenuates endoplasmic reticulum stress-induced apoptotic cell death through deubiquitination and stabilization of FBXO7

Lee,

Chung

2023

PLoS ONE

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Parkinson’s disease (PD) is a common neurodegenerative disease (NDD) characterized by the loss of dopaminergic neurons in the substantia nigra. Similar to other NDDs, the buildup of toxic protein aggregates in PD leads to progressive neuronal loss, culminating in neurodegeneration. Accumulating evidence indicates that alterations in subcellular organelles, particularly the endoplasmic reticulum (ER), are critically involved in pathological neurodegenerative events in NDDs, including PD. Mutations in the F-box only protein 7 (FBXO7 or PARK15) gene have been found to cause early onset autosomal recessive familiar PD. FBXO7 functions as an adaptor protein in the Skp1-Cullin1-F-box protein (SCF) E3 ubiquitin ligase complex, which promotes substrate ubiquitination. Although FBXO7 is involved in the ubiquitination of various target proteins, little is known about the upstream regulatory mechanism of FBXO7 and/or its modulator(s). Ubiquitin specific protease 7 (USP7) is a deubiquitinating enzyme that regulates the balance between protein synthesis and degradation by removing ubiquitin from target substrates. The role of USP7 in various types of cancer is well-established; however, its role in NDDs has not been elucidated to date. In this study, we identified that USP7 acts as a novel regulator of FBXO7, positively regulating the stability of FBXO7 through Lys48-linked deubiquitination. Moreover, USP7 was found to mitigate ER stress-induced cytotoxicity and apoptosis by preventing the proteasomal degradation of FBXO7. Taken together, our study suggests that the functional relationship between FBXO7 and USP7 may play a crucial role in ER stress-induced apoptosis and the pathogenesis of PD.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

USP7 attenuates endoplasmic reticulum stress-induced apoptotic cell death through deubiquitination and stabilization of FBXO7

Lee,

Chung

2023

PLoS ONE

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“…The results of mRNA-seq analysis in cord blood showed that among the top gene list with significant log2 fold changes, only FAM210B, a mitochondrial protein, is known to be linked to erythroid differentiation (Kondo et al 2016 ), whereas KRT1 and FOXO4 are associated with oxidative stress (Yang et al 2022 ; Collard et al 2001 ). Also, TRIM58 and FBXO7 are involved in the ubiquitin-dependent protein catabolic pathway (Lee et al 2023 ). Using DEG, three pathway enrichment analyses, including GO, GSEA, and FGSEA, revealed that the enriched pathways in the High PM 2.5 group were mainly involved in mitochondrial- and apoptosis-related pathways.…”

Section: Discussionmentioning

confidence: 99%

Maternal PM2.5 exposure is associated with preterm birth and gestational diabetes mellitus, and mitochondrial OXPHOS dysfunction in cord blood

You,

Park,

Kwon

et al. 2024

Environ Sci Pollut Res

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Maternal exposure to fine particulate matter (PM2.5) is associated with adverse pregnancy and neonatal health outcomes. To explore the mechanism, we performed mRNA sequencing of neonatal cord blood. From an ongoing prospective cohort, Air Pollution on Pregnancy Outcome (APPO) study, 454 pregnant women from six centers between January 2021 and June 2022 were recruited. Individual PM2.5 exposure was calculated using a time-weighted average model. In the APPO study, age-matched cord blood samples from the High PM2.5 (˃15 ug/m3; n = 10) and Low PM2.5 (≤ 15 ug/m3; n = 30) groups were randomly selected for mRNA sequencing. After selecting genes with differential expression in the two groups (p-value < 0.05 and log2 fold change > 1.5), pathway enrichment analysis was performed, and the mitochondrial pathway was analyzed using MitoCarta3.0. The risk of preterm birth (PTB) increased with every 5 µg/m3 increase of PM2.5 in the second trimester (odds ratio 1.391, p = 0.019) after adjusting for confounding variables. The risk of gestational diabetes mellitus (GDM) increased in the second (odds ratio 1.238, p = 0.041) and third trimester (odds ratio 1.290, p = 0.029), and entire pregnancy (odds ratio 1.295, p = 0.029). The mRNA-sequencing of cord blood showed that genes related to mitochondrial activity (FAM210B, KRT1, FOXO4, TRIM58, and FBXO7) and PTB-related genes (ADIPOR1, YBX1, OPTN, NFkB1, HBG2) were upregulated in the High PM2.5 group. In addition, exposure to high PM2.5 affected mitochondrial oxidative phosphorylation (OXPHOS) and proteins in the electron transport chain, a subunit of OXPHOS. These results suggest that exposure to high PM2.5 during pregnancy may increase the risk of PTB and GDM, and dysregulate PTB-related genes. Alterations in mitochondrial OXPHOS by high PM2.5 exposure may occur not only in preterm infants but also in normal newborns. Further studies with larger sample sizes are required.

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“…Identification of Sirtuin activators have been challenging, however, targeting the degradation of SIRT7 could be a more selective way to limit deleterious effects of SIRT7 loss in aging. A previous study showed that a component of a SCF E3 ubiquitin-protein ligase complex, FBXO7, can target SIRT7 for ubiquitination 68 . Additionally, our proteomic analysis of SIRT7 interactors identified several ubiquitin E3 Ligases ( Fig.…”

Section: Discussionmentioning

confidence: 99%

SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging

Tran,

Gilbert,

Vazquez

et al. 2024

Preprint

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SUMMARYSirtuins, a class of highly conserved histone/protein deacetylases, are heavily implicated in senescence and aging. The regulation of sirtuin proteins is tightly controlled both transcriptionally and translationally and via localization within the cell. While Sirtiun proteins are implicated with aging, how their levels are regulated during aging across cell types and eliciting tissue specific age-related cellular changes is unclear. Here, we demonstrate that SIRT7 is targeted for degradation during senescence and liver aging. To uncover the significance of SIRT7 loss, we performed proteomics analysis and identified a new SIRT7 interactor, the HMG box protein NUCKS1. We found that the NUCKS1 transcription factor is recruited onto chromatin during senescence and this is mediated by SIRT7 loss. Further, depletion of NUCKS1 delayed senescence upon DNA damage leading to reduction of inflammatory gene expression. Examination of NUCKS1 transcriptional regulation during senescence revealed gene targets of transcription factors NFKB1, RELA, and CEBPβ. Consistently, in both Sirt7 KO mouse liver and in naturally aged livers, Nucks1 was recruited to chromatin. Further, Nucks1 was bound at promoters and enhancers of age-related genes, including transcription factor Rela, and, moreover, these bound sites had increased accessibility during aging. Overall, our results uncover NUCKS1 as a novel interactor of SIRT7, and show that loss of SIRT7 during senescence and liver aging promotes NUCKS1 chromatin binding to regulate metabolic and inflammatory genes.

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E3 ligase adaptor FBXO7 contributes to ubiquitination and proteasomal degradation of SIRT7 and promotes cell death in response to hydrogen peroxide

Cited by 8 publications

References 50 publications

USP7 attenuates endoplasmic reticulum stress-induced apoptotic cell death through deubiquitination and stabilization of FBXO7

USP7 attenuates endoplasmic reticulum stress-induced apoptotic cell death through deubiquitination and stabilization of FBXO7

Maternal PM2.5 exposure is associated with preterm birth and gestational diabetes mellitus, and mitochondrial OXPHOS dysfunction in cord blood

SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging

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