Deubiquitinases: Modulators of Different Types of Regulated Cell Death

Lee, Choong Sil; Kim, Seung‐Yeon; Hwang, Gyuho; Song, Jaewhan

doi:10.3390/ijms22094352

Cited by 13 publications

(7 citation statements)

References 232 publications

(312 reference statements)

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“…2b ), suggesting a potential primary role for the ubiquitin-dependent degradation pathway in GPX4 reduction. The ubiquitin-proteasome system (UPS) and deubiquitinating enzymes (DUBs) are critical for cellular protein homeostasis, executing both post-transcriptional degradation and stabilization 18 . They also play a crucial role in ferroptosis and kidney disease pathology 10 , 19 .…”

Section: Resultsmentioning

confidence: 99%

Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury

Chu,

Cao,

Wan

et al. 2023

Nat Commun

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Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.

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Section: Resultsmentioning

confidence: 99%

Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury

Chu,

Cao,

Wan

et al. 2023

Nat Commun

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“…This was performed to investigate the anticancer mechanism of functionalized AuNPs and correlate the critical end points finding (cytotoxicity, ROS, MMP) with that of DUB protein expression. Several studies have shown that targeting DUBs might be an effective approach in cancer therapy due to their significant role in controlling cellular mechanisms such as apoptosis, cell proliferation, DNA transcription and repair, cell cycle progression, immune response, and protein modification. − In this study, the protein expression of DUBs in cancerous A549 and noncancerous MRC-5 lung fibroblast cells without AuNP treatment was first analyzed. It was found that proteins were upregulated in A549 cells compared to MRC-5 which correlated with the proliferation of A549 cells being cancerous cells.…”

Section: Discussionmentioning

confidence: 99%

Functionalized Gold Nanoparticles Suppress the Proliferation of Human Lung Alveolar Adenocarcinoma Cells by Deubiquitinating Enzymes Inhibition

Ibrahim,

Akere,

Chakraborty

et al. 2023

ACS Omega

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Functionalized gold nanoparticles (AuNPs) are widely used in therapeutic applications, but little is known regarding the impact of their surface functionalization in the process of toxicity against cancer cells. This study investigates the anticancer effects of 5 nm spherical AuNPs functionalized with tannate, citrate, and PVP on deubiquitinating enzymes (DUBs) in human lung alveolar adenocarcinoma (A549) cells. Our findings show that functionalized AuNPs reduce the cell viability in a concentration- and time-dependent manner as measured by modified lactate dehydrogenase (mLDH) and 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays. An increased generation of intracellular reactive oxygen species (ROS) and depletion of glutathione (GSH/GSSG) ratio was observed with the highest AuNP concentration of 10 μg/mL. The expression of DUBs such as ubiquitin specific proteases (USP7, USP8, and USP10) was slightly inhibited when treated with concentrations above 2.5 μg/mL. Moreover, functionalized AuNPs showed an inhibitory effect on protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and wingless-related integration site (Wnt) signaling proteins, and this could further trigger mitochondrial related-apoptosis by the upregulation of caspase-3, caspase-9, and PARP in A549 cells. Furthermore, our study shows a mechanistic understanding of how functionalized AuNPs inhibit the DUBs, consequently suppressing cell proliferation, and can be modulated as an approach toward anticancer therapy. The study also warrants the need for future work to investigate the effect of functionalized AuNPs on DUB on other cancer cell lines both in vitro and in vivo.

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“…In addition, a previous study reported that K128E of Bax has the potential to alter the release of cytochrome c, and the point mutations of Bax prevent apoptosis-inducing functions [ 46 ]. The importance of the role of DUBs has been emphasized, and it is known that DUB functions in apoptosis and aging-related diseases, including neurodegenerative diseases [ 47 , 48 ]. Research on these DUBs should therefore continue for cancers or neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinating Enzyme USP12 Regulates the Pro-Apoptosis Protein Bax

Choi

Lim

Baek

2022

IJMS

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The Bax protein is a pro-apoptotic protein belonging to the Bcl-2 family, involved in inducing apoptosis at the mitochondrial level. Regulating the protein levels of Bax is essential to enhancing apoptosis. In the current study, we ascertained the presence of deubiquitinating enzymes (DUBs) associated with Bax by performing the yeast two-hybrid screening (Y2H). We determined that ubiquitin-specific protease 12 (USP12), one of the DUBs, is associated with Bax. The binding of USP12 to Bax shows the interaction as a DUB, which regulates ubiquitination on Bax. Taken together, we believe that USP12 regulates Bax by detaching ubiquitin on K63-linked chains, indicating that USP12 affects the cellular functions of Bax, but it is not related with proteasomal degradation. The half-life of the Bax protein was determined by performing the site-directed mutagenesis of putative ubiquitination sites on Bax (K128R, K189R, and K190R). Of these, Bax (K128R and K190R) showed less ubiquitination; therefore, we compared the half-life of Bax (WT) and Bax K mutant forms in vitro. Interestingly, Bax (K189R) showed a higher ubiquitination level and shorter half-life than Bax (WT), and the (K128R and K190R) mutant form has a longer half-life than Bax (WT).

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Deubiquitinases: Modulators of Different Types of Regulated Cell Death

Cited by 13 publications

References 232 publications

Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury

Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury

Functionalized Gold Nanoparticles Suppress the Proliferation of Human Lung Alveolar Adenocarcinoma Cells by Deubiquitinating Enzymes Inhibition

Deubiquitinating Enzyme USP12 Regulates the Pro-Apoptosis Protein Bax

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