P65 mediated UBR4 in exosomes derived from menstrual blood stromal cells to reduce endometrial fibrosis by regulating YAP Ubiquitination

Qi, Jiarui; Zhang, Xudong; Zhang, Siwen; Wu, Shanshan; Lu, Yimeng; Li, Shuyu; Li, Pingping; Tan, Jichun

doi:10.1186/s12951-023-02070-3

Cited by 4 publications

(2 citation statements)

References 56 publications

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“…The discovery that ubiquitination targets proteins for proteasomal degradation earned the Nobel Prize in Chemistry in 2004. The elucidation of ubiquitination and its functions has enriched our understanding of the complete journey of a protein’s life cycle - from translation initiation, localization to specific cellular compartments for function, to eventual degradation within the proteasome ( Qi et al, 2023 ). This comprehensive view allows us to witness the journey from protein “infancy” to mature functionality and finally to its “senescent” state.…”

Section: Discussionmentioning

confidence: 99%

OTUD3 suppresses the mTORC1 signaling by deubiquitinating KPTN

Li,

Yang,

Lin

et al. 2024

Front. Pharmacol.

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Background: Ubiquitination and deubiquitination modifications play pivotal roles in eukaryotic life processes, regulating protein dynamics via the ubiquitin-proteasome pathway. Dysregulation can impact disease development, including cancer and neurodegenerative disorders. Increasing evidence highlights their role in tumorigenesis, modulating key proteins. OTUD3, a deubiquitinase, stabilizes PTEN, suppressing tumor growth by inhibiting PI3K-AKT signaling. Yet, further OTUD3 substrates remain underexplored.Methods: We employed the In vivo ubiquitination assay to investigate the ubiquitination role of OTUD3 on KPTN within the cellular context. Additionally, CRISPR/Cas9 editing and Immunofluorescence were utilized to study the impact of OTUD3 on the mTOR signaling pathway in cells. Furthermore, Cell proliferation assay and NMR were employed to explore the effects of OTUD3 on cellular growth and proliferation.Results: OTUD3 serves as a deubiquitinase for KPTN. OTUD3 interacts with KPTN, facilitated by the OTU domain within OTUD3. Further investigations confirmed KPTN’s ubiquitination modification, primarily at lysine residue 49. Ubiquitination experiments demonstrated OTUD3’s ability to mediate KPTN’s deubiquitination without affecting its protein levels. This suggests KPTN’s ubiquitination is a function-regulated, non-degradable modification. Under various amino acid starvation or stimulation conditions, overexpressing OTUD3 reduces mTORC1 signaling activation, while knocking out OTUD3 further enhances it. Notably, OTUD3’s regulation of mTORC1 signaling relies on its deubiquitinase activity, and this effect is observed even in PTEN KO cells, confirming its independence from PTEN, a reported substrate. OTUD3 also promotes GATOR1’s lysosomal localization, a process requiring KPTN’s involvement. Ultimately, OTUD3 affects cellular metabolic pool products by downregulating the mTORC1 pathway, significantly inhibiting tumor cell growth and proliferation.Discussion: Our experiments shed light on an alternative perspective regarding the intrinsic functions of OTUD3 in inhibiting tumor development. We propose a novel mechanism involving KPTN-mediated regulation of the mTORC1 signaling pathway, offering fresh insights into the occurrence and progression of tumor diseases driven by related genes. This may inspire new approaches for drug screening and cancer treatment, potentially guiding future therapies for relevant tumors.

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Section: Discussionmentioning

confidence: 99%

OTUD3 suppresses the mTORC1 signaling by deubiquitinating KPTN

Li,

Yang,

Lin

et al. 2024

Front. Pharmacol.

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“…Therefore, MenSCs are more suitable source of MSCs for stem cell therapy, and consistently with previous reports ( Zheng et al, 2018 ; Chang et al, 2020 ), show ability to help repair endometrial damage and alleviate symptoms of IUA in a rat model. Beyond using MenSCs directly, a recent study used MenSCs-derived exosomes and found prevention of endometrial fibrosis in IUA model via modulating YAP ubiquitination ( Zhang et al, 2019 ; Qi et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

VitroGel-loaded human MenSCs promote endometrial regeneration and fertility restoration

Wu,

Tan

et al. 2024

Front. Bioeng. Biotechnol.

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Introduction: Intrauterine adhesions (IUA), also known as Asherman's syndrome, is caused by trauma to the pregnant or non-pregnant uterus, which leads to damaged endometrial basal lining and partial or total occlusion of the uterine chambers, resulting in abnormal menstruation, infertility, or recurrent miscarriage. The essence of this syndrome is endometrial fibrosis. And there is no effective treatment for IUA to stimulate endometrial regeneration currently. Recently, menstrual blood-derived stem cells (MenSCs) have been proved to hold therapeutic promise in various diseases, such as myocardial infarction, stroke, diabetes, and liver cirrhosis.Methods: In this study, we examined the effects of MenSCs on the repair of uterine adhesions in a rat model, and more importantly, promoted such therapeutic effects via a xeno-free VitroGel MMP carrier.Results: This combined treatment reduced the expression of inflammatory factors, increased the expression of anti-inflammatory factors, restricted the area of endometrial fibrosis, diminished uterine adhesions, and partially restored fertility, showing stronger effectiveness than each component alone and almost resembling the sham group.Discussion: Our findings suggest a highly promising strategy for IUA treatment.

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