The E3 ubiquitin ligase Mule acts through the ATM–p53 axis to maintain B lymphocyte homeostasis

Zhou, Hao; Duncan, Gordon S.; Yu, Shi; Li, Wanda Y.; Silvester, Jennifer; Hong, Claire; You, Han; Brenner, Dirk; Gorrini, Chiara; Haight, Jillian; Wakeham, Andrew; You-Ten, Annick; McCracken, Susan; Elia, Andrew; Li, Qinxi; Detmar, Jacqui; Jurisicova, Andrea; Hobeika, Elias; Reth, Michael; Sheng, Yi; Lang, Philipp A.; Ohashi, Pamela S.; Zhong, Qing; Wang, Xiaodong; Mak, Tak W.

doi:10.1084/jem.20111363

Cited by 58 publications

(99 citation statements)

References 44 publications

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“…This protection was not associated with a significant difference in expression of GLUT2, which is required for STZ action. Rather, these findings suggest that HUWE1 can regulate substrates such as p53 differently in specific settings, similar to the recent report on the dual role of HUWE1 in regulation of B lymphocyte survival and proliferation [17]. HUWE1 demonstrated similar dual function in pancreatic beta cells, depending on the experimental context in which the role of HUWE1 was examined.…”

Section: Discussionsupporting

confidence: 87%

“…This difference is reflected in the early embryonic lethality (E12.5) of the whole-body knockout using the targeting construct used in our study, whereas perinatal lethality was observed by Kon et al [17,34]. These differences suggest a more complete genetic ablation in mice that we used for our study in comparison to the report by Kon et al [17,34].…”

Section: Discussioncontrasting

confidence: 56%

“…Furthermore, the region of the Huwe1 gene that was targeted was different between the two groups (loxP sites flanked exon 11 in the report by Kon et al, whereas we used mice with loxP sites flanking exons 76 and 77) [34]. This difference is reflected in the early embryonic lethality (E12.5) of the whole-body knockout using the targeting construct used in our study, whereas perinatal lethality was observed by Kon et al [17,34]. These differences suggest a more complete genetic ablation in mice that we used for our study in comparison to the report by Kon et al [17,34].…”

Section: Discussionmentioning

confidence: 81%

“…As such, HUWE1-deficient B lymphocytes demonstrated reduced viability under basal condition, while under genotoxic stress, they were resistant to apoptosis [17]. To test whether this context-dependent divergent biological role of HUWE1 occurred in pancreatic beta cells, we used an MLDS model to induce beta cell apoptosis in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…One such molecule is myeloid cell leukaemia sequence 1 (MCL1) ubiquitin ligase E3 (MULE) or HECT, UBA and WWE domain containing 1, E3 ubiquitin protein ligase (HUWE1 [also known as ARF-BP1 or LASU1]). The Huwe1 gene is encoded on the X-chromosome and its protein product contains multiple domains, including BH3, which allows for polyubiquitination and degradation of p53 independent of MDM2 [17]. Thus, HUWE1 may have a regulatory role in p53-mediated apoptosis of beta cells that occurs during diabetogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Dichotomous role of pancreatic HUWE1/MULE/ARF-BP1 in modulating beta cell apoptosis in mice under physiological and genotoxic conditions

et al. 2014

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Aims/hypothesis Diabetes mellitus represents a significant burden on the health of the global population. Both type 1 and type 2 diabetes share a common feature of a reduction in functional beta cell mass. A newly discovered ubiquitination molecule HECT, UBA and WWE domain containing 1, E3 ubiquitin protein ligase (HUWE1 [also known as MULE or ARF-BP1]) is a critical regulator of p53-dependent apoptosis. However, its role in islet homeostasis is not entirely clear. Methods We generated mice with pancreas-specific deletion of Huwe1 using a Cre-loxP recombination system driven by the Pdx1 promoter (Pdx1cre + Huwe1 fl/fl ) to assess the in vivo role of HUWE1 in the pancreas. Results Targeted deletion of Huwe1 in the pancreas preferentially activated p53-mediated beta cell apoptosis, leading to reduced beta cell mass and diminished insulin exocytosis. These defects were aggravated by ageing, with progressive further decline in insulin secretion and glucose homeostasis in older mice. Intriguingly, Huwe1 deletion provided protection against genotoxicity, such that Pdx1cre + Huwe1 fl/fl mice were resistant to multiple-lowdose-streptozotocin-induced beta cell apoptosis and diabetes. Conclusion/interpretation HUWE1 expression in the pancreas is essential in determining beta cell mass. Furthermore, HUWE1 demonstrated divergent roles in regulating beta cell apoptosis depending on physiological or genotoxic conditions.

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Section: Discussionsupporting

confidence: 87%

Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dichotomous role of pancreatic HUWE1/MULE/ARF-BP1 in modulating beta cell apoptosis in mice under physiological and genotoxic conditions

et al. 2014

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E3 Ubiquitin Ligases as Molecular Machines and Platforms for Drug Development

Ioris

Ferris

D’Angiolella

2022

Inducing Targeted Protein Degradation

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The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress glioblastoma progression

Yuan

Wang

Zhao

et al. 2022

Cancer Communications

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Background Elucidation of the post‐transcriptional modification has led to novel strategies to treat intractable tumors, especially glioblastoma (GBM). The ubiquitin‐proteasome system (UPS) mediates a reversible, stringent and stepwise post‐translational modification which is closely associated with malignant processes of GBM. To this end, developing novel therapeutic approaches to target the UPS may contribute to the treatment of this disease. This study aimed to screen the vital and aberrantly regulated component of the UPS in GBM. Based on the molecular identification, functional characterization, and mechanism investigation, we sought to elaborate a novel therapeutic strategy to target this vital factor to combat GBM. Methods We combined glioma datasets and human patient samples to screen and identify aberrantly regulated E3 ubiquitin ligase. Multidimensional database analysis and molecular and functional experiments in vivo and in vitro were used to evaluate the roles of HECT, UBA and WWE domain‐containing E3 ubiquitin ligase 1 (HUWE1) in GBM. dCas9 synergistic activation mediator system and recombinant adeno‐associated virus (rAAV) were used to endogenously overexpress full‐length HUWE1 in vitro and in glioma orthotopic xenografts. Results Low expression of HUWE1 was closely associated with worse prognosis of GBM patients. The ubiquitination and subsequent degradation of N‐Myc mediated by HUWE1, leading to the inactivation of downstream Delta‐like 1 (DLL1)‐NOTCH1 signaling pathways, inhibited the proliferation, invasion, and migration of GBM cells in vitro and in vivo. A rAAV dual‐vector system for packaging and delivery of dCas9‐VP64 was used to augment endogenous HUWE1 expression in vivo and showed an antitumor activity in glioma orthotopic xenografts. Conclusions The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress GBM progression. Antitumor activity of rAAV dual‐vector delivering dCas9‐HUWE1 system uncovers a promising therapeutic strategy for GBM.

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The E3 ubiquitin ligase Mule acts through the ATM–p53 axis to maintain B lymphocyte homeostasis

Abstract: Genetic manipulation reveals that Mule is vital for B cell development, proliferation, and homeostasis as a result of its ability to regulate p53 and ATM.

Cited by 58 publications

References 44 publications

Dichotomous role of pancreatic HUWE1/MULE/ARF-BP1 in modulating beta cell apoptosis in mice under physiological and genotoxic conditions

Dichotomous role of pancreatic HUWE1/MULE/ARF-BP1 in modulating beta cell apoptosis in mice under physiological and genotoxic conditions

E3 Ubiquitin Ligases as Molecular Machines and Platforms for Drug Development

The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress glioblastoma progression

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