The Role of E3 Ligase Pirh2 in Disease

Daks, Alexandra; Fedorova, Olga; Parfenyev, Sergey; Nevzorov, Ivan; Shuvalov, Oleg; Barlev, Nickolai A.

doi:10.3390/cells11091515

Cited by 6 publications

(5 citation statements)

References 204 publications

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“…S1 ). Human PIRH2 regulates p53 and other transcription factors in the nucleus and is implicated in diseases including cancer ( 40 , 52 ). Because human PIRH2 displayed high sequence ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Our data suggest that MIEL1 ubiquitinates seed oleosins in the vicinity of a peroxisome for proteasomal degradation during germination. The human MIEL1 homolog (PIRH2; p 53- i nduced protein with a R ING- H2 domain) regulates p53 and promotes tumorigenesis ( 40 ). Like MIEL1, PIRH2 localized to peroxisomes when expressed in Arabidopsis , hinting at previously unexplored roles for PIRH2 in humans.…”

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confidence: 99%

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The ubiquitin-protein ligase MIEL1 localizes to peroxisomes to promote seedling oleosin degradation and lipid droplet mobilization

Traver

Bartel

2023

Proc. Natl. Acad. Sci. U.S.A.

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Lipid droplets are organelles conserved across eukaryotes that store and release neutral lipids to regulate energy homeostasis. In oilseed plants, fats stored in seed lipid droplets provide fixed carbon for seedling growth before photosynthesis begins. As fatty acids released from lipid droplet triacylglycerol are catabolized in peroxisomes, lipid droplet coat proteins are ubiquitinated, extracted, and degraded. In Arabidopsis seeds, the predominant lipid droplet coat protein is OLEOSIN1 (OLE1). To identify genes modulating lipid droplet dynamics, we mutagenized a line expressing mNeonGreen-tagged OLE1 expressed from the OLE1 promoter and isolated mutants with delayed oleosin degradation. From this screen, we identified four miel1 mutant alleles. MIEL1 (MYB30-interacting E3 ligase 1) targets specific MYB transcription factors for degradation during hormone and pathogen responses [D. Marino et al ., Nat. Commun. 4 , 1476 (2013); H. G. Lee and P. J. Seo, Nat. Commun. 7 , 12525 (2016)] but had not been implicated in lipid droplet dynamics. OLE1 transcript levels were unchanged in miel1 mutants, indicating that MIEL1 modulates oleosin levels posttranscriptionally. When overexpressed, fluorescently tagged MIEL1 reduced oleosin levels, causing very large lipid droplets. Unexpectedly, fluorescently tagged MIEL1 localized to peroxisomes. Our data suggest that MIEL1 ubiquitinates peroxisome-proximal seed oleosins, targeting them for degradation during seedling lipid mobilization. The human MIEL1 homolog (PIRH2; p53-induced protein with a RING-H2 domain) targets p53 and other proteins for degradation and promotes tumorigenesis [A. Daks et al ., Cells 11 , 1515 (2022)]. When expressed in Arabidopsis , human PIRH2 also localized to peroxisomes, hinting at a previously unexplored role for PIRH2 in lipid catabolism and peroxisome biology in mammals.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The ubiquitin-protein ligase MIEL1 localizes to peroxisomes to promote seedling oleosin degradation and lipid droplet mobilization

Traver

Bartel

2023

Proc. Natl. Acad. Sci. U.S.A.

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“…It is possible that pelitinib may directly or indirectly target RNF8, leading to the decrease in Twist1 stability. In addition, Twist1 is degraded by other E3 ligases, including Pirh2 and tumor necrosis factor receptor-associated factor-interacting protein [ 58 , 59 ]. Considering the findings reported to date, these E3 ligases target only Twist1 and induce its degradation by ubiquitination.…”

Section: Discussionmentioning

confidence: 99%

Role of pelitinib in the regulation of migration and invasion of hepatocellular carcinoma cells via inhibition of Twist1

et al. 2023

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Background Overexpression of Twist1, one of the epithelial-mesenchymal transition-transcription factors (EMT-TFs), is associated with hepatocellular carcinoma (HCC) metastasis. Pelitinib is known to be an irreversible epidermal growth factor receptor tyrosine kinase inhibitor that is used in clinical trials for colorectal and lung cancers, but the role of pelitinib in cancer metastasis has not been studied. This study aimed to investigate the anti-migration and anti-invasion activities of pelitinib in HCC cell lines. Methods Using three HCC cell lines (Huh7, Hep3B, and SNU449 cells), the effects of pelitinib on cell cytotoxicity, invasion, and migration were determined by cell viability, wound healing, transwell invasion, and spheroid invasion assays. The activities of MMP-2 and -9 were examined through gelatin zymography. Through immunoblotting analyses, the expression levels of EMT-TFs (Snail1, Twist1, and ZEB1) and EMT-related signaling pathways such as mitogen-activated protein kinases (MAPKs) and Akt signaling pathways were measured. The activity and expression levels of target genes were analyzed by reporter assay, RT-PCR, quantitative RT-PCR, and immunoblotting analysis. Statistical analysis was performed using one-way ANOVA with Dunnett's Multiple comparison tests in Prism 3.0 to assess differences between experimental conditions. Results In this study, pelitinib treatment significantly inhibited wound closure in various HCC cell lines, including Huh7, Hep3B, and SNU449. Additionally, pelitinib was found to inhibit multicellular cancer spheroid invasion and metalloprotease activities in Huh7 cells. Further investigation revealed that pelitinib treatment inhibited the migration and invasion of Huh7 cells by inducing Twist1 degradation through the inhibition of MAPK and Akt signaling pathways. We also confirmed that the inhibition of cell motility by Twist1 siRNA was similar to that observed in pelitinib-treated group. Furthermore, pelitinib treatment regulated the expression of target genes associated with EMT, as demonstrated by the upregulation of E-cadherin and downregulation of N-cadherin. Conclusion Based on our novel finding of pelitinib from the perspective of EMT, pelitinib has the ability to inhibit EMT activity of HCC cells via inhibition of Twist1, and this may be the potential mechanism of pelitinib on the suppression of migration and invasion of HCC cells. Therefore, pelitinib could be developed as a potential anti-cancer drug for HCC.

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“…HUWE1 knockdown results in stabilization of CHK1 and the regulation of the DDR signaling pathway [ 117 ]. PIRH2 and SIAH2 have also been shown to regulate the stability of CHK2, with significant consequences on cell cycle control involved in DDR [ 118 , 119 ].…”

Section: Degradation Of Critical Proteins In Dna Damage Repair-mediat...mentioning

confidence: 99%

Protein degradation: expanding the toolbox to restrain cancer drug resistance

Hui

Jiang

et al. 2023

J Hematol Oncol

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Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain drug resistance has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib and proteolysis-targeting chimeric have been developed. Compared with intervention at the transcriptional level, targeting the degradation process seems to be a more rapid and direct strategy. Proteasomal proteolysis and lysosomal proteolysis are the most critical quality control systems responsible for the degradation of proteins or organelles. Although proteasomal and lysosomal inhibitors (e.g., bortezomib and chloroquine) have achieved certain improvements in some clinical application scenarios, their routine application in practice is still a long way off, which is due to the lack of precise targeting capabilities and inevitable side effects. In-depth studies on the regulatory mechanism of critical protein degradation regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), and chaperones, are expected to provide precise clues for developing targeting strategies and reducing side effects. Here, we discuss the underlying mechanisms of protein degradation in regulating drug efflux, drug metabolism, DNA repair, drug target alteration, downstream bypass signaling, sustaining of stemness, and tumor microenvironment remodeling to delineate the functional roles of protein degradation in drug resistance. We also highlight specific E3 ligases, DUBs, and chaperones, discussing possible strategies modulating protein degradation to target cancer drug resistance. A systematic summary of the molecular basis by which protein degradation regulates tumor drug resistance will help facilitate the development of appropriate clinical strategies.

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The Role of E3 Ligase Pirh2 in Disease

Cited by 6 publications

References 204 publications

The ubiquitin-protein ligase MIEL1 localizes to peroxisomes to promote seedling oleosin degradation and lipid droplet mobilization

The ubiquitin-protein ligase MIEL1 localizes to peroxisomes to promote seedling oleosin degradation and lipid droplet mobilization

Role of pelitinib in the regulation of migration and invasion of hepatocellular carcinoma cells via inhibition of Twist1

Protein degradation: expanding the toolbox to restrain cancer drug resistance

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