scholarly journals miR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin Ligase

2020 ◽  
Vol 21 (1) ◽  
pp. 355 ◽  
Author(s):  
Anthea Di Rita ◽  
Teresa Maiorino ◽  
Krenare Bruqi ◽  
Floriana Volpicelli ◽  
Gian Carlo Bellenchi ◽  
...  
Keyword(s):  
Protein Content ◽  
Ubiquitin Ligase ◽  
Therapeutic Target ◽  
Feedback Loop ◽  
E3 Ubiquitin Ligase ◽  
Human Diseases ◽  
Mrna Levels ◽  
Cellular Homeostasis ◽  
Promising Therapeutic Target ◽  
Selective Elimination

The selective elimination of dysfunctional mitochondria through mitophagy is crucial for preserving mitochondrial quality and cellular homeostasis. The most described mitophagy pathway is regulated by a positive ubiquitylation feedback loop in which the PINK1 (PTEN induced kinase 1) kinase phosphorylates both ubiquitin and the E3 ubiquitin ligase PRKN (Parkin RBR E3 ubiquitin ligase), also known as PARKIN. This event recruits PRKN to the mitochondria, thus amplifying ubiquitylation signal. Here we report that miR-218 targets PRKN and negatively regulates PINK1/PRKN-mediated mitophagy. Overexpression of miR-218 reduces PRKN mRNA levels, thus also reducing protein content and deregulating the E3 ubiquitin ligase action. In fact, following miR-218 overexpression, mitochondria result less ubiquitylated and the autophagy machinery fails to proceed with correct mitochondrial clearance. Since mitophagy defects are associated with various human diseases, these results qualify miR-218 as a promising therapeutic target for human diseases.

scholarly journals TFEB activates Nrf2 by repressing its E3 ubiquitin ligase DCAF11 and promoting phosphorylation of p62

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jee-Yun Park ◽  
Sunhyo Kim ◽  
Hee Young Sohn ◽  
Young Ho Koh ◽  
Chulman Jo
Keyword(s):  
Oxidative Stress ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Biological Response ◽  
Related Factor ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Glutathione S Transferase ◽  
First Time ◽  
Cellular Stressors

Abstract Transcriptional factor EB (TFEB) and nuclear factor E2-related factor 2 (Nrf2) play crucial roles in the biological response against cellular stressors; however, their relationship has not yet been investigated. Here, we constructed human neuroglioma cell lines stably expressing TFEB. The expression of Nrf2-response genes, including heme oxygenase (HO)-1, glutathione-s-transferase-mu1 (GSTM1), and p62, was induced in the cell line, independent of oxidative stress. Of note, the protein level of Nrf2 was significantly increased, and its ubiquitinated fraction was reduced in stable cells compared to that in the control cells. Among E3 ubiquitin ligases known to be involved in the ubiquitination of Nrf2, DDB1 and Cullin4 associated factor 11 (DCAF11) was down-regulated at both protein and mRNA levels in stable cells, indicating that the repression of DCAF11 by TFEB may be mainly involved in the stabilization of Nrf2. In addition, the level of phosphorylated p62 at S349 was highly increased in stable cells compared to that in control cells, which could allow it to interfere with the association of Keap1 and Nrf2, thus stabilizing Nrf2. We suggest for the first time that TFEB could activate Nrf2 by increasing its stability under conditions devoid of oxidative stress.

scholarly journals WNK regulates Wnt signalling and β-Catenin levels by interfering with the interaction between β-Catenin and GID

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Atsushi Sato ◽  
Masahiro Shimizu ◽  
Toshiyasu Goto ◽  
Hiroyuki Masuno ◽  
Hiroyuki Kagechika ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Therapeutic Target ◽  
E3 Ubiquitin Ligase ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Tumour Development ◽  
Wnt Signalling Pathway

Abstractβ-Catenin is an important component of the Wnt signalling pathway. As dysregulation or mutation of this pathway causes many diseases, including cancer, the β-Catenin level is carefully regulated by the destruction complex in the Wnt signalling pathway. However, the mechanisms underlying the regulation of β-Catenin ubiquitination and degradation remain unclear. Here, we find that WNK (With No Lysine [K]) kinase is a potential regulator of the Wnt signalling pathway. We show that WNK protects the interaction between β-Catenin and the Glucose-Induced degradation Deficient (GID) complex, which includes an E3 ubiquitin ligase targeting β-Catenin, and that WNK regulates the β-Catenin level. Furthermore, we show that WNK inhibitors induced β-Catenin degradation and that one of these inhibitors suppressed xenograft tumour development in mice. These results suggest that WNK is a previously unrecognized regulator of β-Catenin and a therapeutic target of cancer.

scholarly journals TRIP13 promotes the cell proliferation, migration and invasion of glioblastoma through the FBXW7/c-MYC axis

2019 ◽  
Vol 121 (12) ◽  
pp. 1069-1078 ◽  
Author(s):  
Guanghui Zhang ◽  
Qingzong Zhu ◽  
Gang Fu ◽  
Jianbing Hou ◽  
Xiaosong Hu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Therapeutic Target ◽  
Biological Effect ◽  
Thyroid Hormone Receptor ◽  
E3 Ubiquitin Ligase ◽  
Mitotic Checkpoint ◽  
Migration And Invasion ◽  
Cell Models ◽  
Aaa Atpase

Abstract Background Thyroid hormone receptor interactor 13 (TRIP13) is an AAA + ATPase that plays an important role in the mitotic checkpoint. TRIP13 is highly expressed in various human tumours and promotes tumorigenesis. However, the biological effect of TRIP13 in GBM cells remains unclear. Methods We generated GBM cell models with overexpressed or silenced TRIP13 via lentivirus-mediated overexpression and RNAi methods. The biological role of TRIP13 in the proliferation, migration and invasion of GBM cells has been further explored. Results Our research indicated that TRIP13 was highly expressed in GBM tissues and cells. We found that the proliferation, migration and invasion abilities were inhibited in TRIP13-knockdown GBM cells. These results indicated that TRIP13 plays an important role in the tumorigenesis of GBM. Moreover, we found that TRIP13 first stabilised c-MYC by inhibiting the transcription of FBXW7, which is an E3 ubiquitin ligase of c-MYC, by directly binding to the promoter region of FBXW7. Therefore, our study indicated that the TRIP13/FBXW7/c-MYC pathway might provide a prospective therapeutic target in the treatment of GBM. Conclusions These results indicated that TRIP13 plays an oncogenic role in GBM. The TRIP13/FBXW7/c-MYC pathway might act as a prospective therapeutic target for GBM patients.

scholarly journals PELI1 functions as a dual modulator of necroptosis and apoptosis by regulating ubiquitination of RIPK1 and mRNA levels of c-FLIP

2017 ◽  
Vol 114 (45) ◽  
pp. 11944-11949 ◽  
Author(s):  
Huibing Wang ◽  
Huyan Meng ◽  
Xingyan Li ◽  
Kezhou Zhu ◽  
Kangyun Dong ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Kinase Activity ◽  
E3 Ubiquitin Ligase ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Distinct Cell ◽  
Regulated Expression ◽  
Cell Death Mechanisms ◽  
Induced Apoptosis ◽  
Downstream Mediator

Apoptosis and necroptosis are two distinct cell death mechanisms that may be activated in cells on stimulation by TNFα. It is still unclear, however, how apoptosis and necroptosis may be differentially regulated. Here we screened for E3 ubiquitin ligases that could mediate necroptosis. We found that deficiency of Pellino 1 (PELI1), an E3 ubiquitin ligase, blocked necroptosis. We show that PELI1 mediates K63 ubiquitination on K115 of RIPK1 in a kinase-dependent manner during necroptosis. Ubiquitination of RIPK1 by PELI1 promotes the formation of necrosome and execution of necroptosis. Although PELI1 is not directly involved in mediating the activation of RIPK1, it is indispensable for promoting the binding of activated RIPK1 with its downstream mediator RIPK3 to promote the activation of RIPK3 and MLKL. Inhibition of RIPK1 kinase activity blocks PELI1-mediated ubiquitination of RIPK1 in necroptosis. However, we show that PELI1 deficiency sensitizes cells to both RIPK1-dependent and RIPK1-independent apoptosis as a result of down-regulated expression of c-FLIP, an inhibitor of caspase-8. Finally, we show thatPeli1−/−mice are sensitized to TNFα-induced apoptosis. Thus, PELI1 is a key modulator of RIPK1 that differentially controls the activation of necroptosis and apoptosis.

scholarly journals Oestrogen causes ATBF1 protein degradation through the oestrogen-responsive E3 ubiquitin ligase EFP

2012 ◽  
Vol 444 (3) ◽  
pp. 581-590 ◽  
Author(s):  
Xue-Yuan Dong ◽  
Xiaoying Fu ◽  
Songqing Fan ◽  
Peng Guo ◽  
Dan Su ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Degradation ◽  
Ubiquitin Ligase ◽  
Feedback Loop ◽  
E3 Ubiquitin Ligase ◽  
Breast Development ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Dependent Cell ◽  
Proteasome Pathway

We reported previously that the tumour suppressor ATBF1 (AT motif-binding factor 1) formed an autoregulatory feedback loop with oestrogen–ERα (oestrogen receptor α) signalling to regulate oestrogen-dependent cell proliferation in breast cancer cells. In this loop ATBF1 inhibits the function of oestrogen–ERα signalling, whereas ATBF1 protein levels are fine-tuned by oestrogen-induced transcriptional up-regulation as well as UPP (ubiquitin–proteasome pathway)-mediated protein degradation. In the present study we show that EFP (oestrogen-responsive finger protein) is an E3 ubiquitin ligase mediating oestrogen-induced ATBF1 protein degradation. Knockdown of EFP increases ATBF1 protein levels, whereas overexpression of EFP decreases ATBF1 protein levels. EFP interacts with and ubiquitinates ATBF1 protein. Furthermore, we show that EFP is an important factor in oestrogen-induced ATBF1 protein degradation in which some other factors are also involved. In human primary breast tumours the levels of ATBF1 protein are positively correlated with the levels of EFP protein, as both are directly up-regulated ERα target gene products. However, the ratio of ATBF1 protein to EFP protein is negatively correlated with EFP protein levels. Functionally, ATBF1 antagonizes EFP-mediated cell proliferation. These findings not only establish EFP as the E3 ubiquitin ligase for oestrogen-induced ATBF1 protein degradation, but further support the autoregulatory feedback loop between ATBF1 and oestrogen–ERα signalling and thus implicate ATBF1 in oestrogen-dependent breast development and carcinogenesis.

scholarly journals The E3 ubiquitin ligase seven in absentia homolog 1 may be a potential new therapeutic target for Parkinson′s disease

2015 ◽  
Vol 10 (8) ◽  
pp. 1286 ◽  
Author(s):  
Zeng-lin Cai ◽  
Jing Xu ◽  
Shou-ru Xue ◽  
Yuan-yuan Liu ◽  
Yong-jin Zhang ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Therapeutic Target ◽  
E3 Ubiquitin Ligase ◽  
Seven In Absentia

scholarly journals The Hh pathway promotes cell apoptosis through Ci-Rdx-Diap1 axis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Bin Liu ◽  
Yan Ding ◽  
Bing Sun ◽  
Qingxin Liu ◽  
Zizhang Zhou ◽  
...  
Keyword(s):  
Birth Defects ◽  
Ubiquitin Ligase ◽  
Cell Apoptosis ◽  
Target Gene ◽  
Regulatory Mechanism ◽  
E3 Ubiquitin Ligase ◽  
Human Diseases ◽  
Induced Apoptosis ◽  
Tumor Drugs ◽  
Transcriptional Target

AbstractApoptosis is a strictly coordinated process to eliminate superfluous or damaged cells, and its deregulation leads to birth defects and various human diseases. The regulatory mechanism underlying apoptosis still remains incompletely understood. To identify novel components in apoptosis, we carry out a modifier screen and find that the Hh pathway aggravates Hid-induced apoptosis. In addition, we reveal that the Hh pathway triggers apoptosis through its transcriptional target gene rdx, which encodes an E3 ubiquitin ligase. Rdx physically binds Diap1 to promote its K63-linked polyubiquitination, culminating in attenuating Diap1−Dronc interaction without affecting Diap1 stability. Taken together, our findings unexpectedly uncover the oncogenic Hh pathway is able to promote apoptosis through Ci-Rdx-Diap1 module, raising a concern to choose Hh pathway inhibitors as anti-tumor drugs.

scholarly journals The parkinsonism-associated protein FBXO7 cooperates with the BAG6 complex in proteasome function and controls the subcellular localization of the complex

2021 ◽  
Author(s):  
Quan Wang ◽  
Vanessa Crnković ◽  
Christian Preisinger ◽  
Judith Stegmüller
Keyword(s):  
Subcellular Localization ◽  
Parkinson Disease ◽  
Ubiquitin Ligase ◽  
Early Onset ◽  
E3 Ubiquitin Ligase ◽  
Proteasome Activity ◽  
Cytoplasmic Localization ◽  
Cellular Homeostasis ◽  
Ubiquitin Ligase Activity ◽  
F Box Protein

The regulation of proteasome activity is essential to cellular homeostasis and defects have been implicated in various disorders including Parkinson disease. The F-box protein FBXO7 has been implicated in early-onset parkinsonism and has previously been shown to have a regulatory role in proteasome activity and assembly. Here, we report the association of the E3 ubiquitin ligase FBXO7-SCF (SKP1, cullin-1, F-box protein) with the BAG6 complex, consisting of the subunits BAG6, GET4 and UBL4A. We identify the subunit GET4 as a direct interactor of FBXO7 and we show that the subunits GET4 and UBL4A are required for proper proteasome activity. Our findings demonstrate reduced binding of FBXO7 variants to GET4 and that FBXO7 variants bring about reduced proteasome activity. In addition, we find that GET4 is a non-proteolytic substrate of FBXO7, that binding of GET4 to BAG6 is enhanced in the presence of active FBXO7-SCF and that the cytoplasmic localization of the BAG6 complex is dependent on the E3 ubiquitin ligase activity. Taken together, our study shows that the parkinsonism-associated FBXO7 cooperates with the BAG6 complex in proteasome function and determines the subcellular localization of this complex.

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