OTUB1 promotes osteoblastic bone formation through stabilizing FGFR2

Fu, Yesheng; Chu, Chun-Ping; Ding, Yi; Deng, Zhikang; Ning, Chao; Hu, Fan; Qiu, Chen; Yu, Biyue; Zhou, Xuemei; Guan, Yang; Jiang, Peng; Zou, Weiguo; Liu, Cui Hua; Zhang, Lingqiang

doi:10.1038/s41392-023-01354-2

Cited by 18 publications

(14 citation statements)

References 58 publications

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“…In addition, the intracellular stability of FGFR2 is maintained by OTUB1, which inhibits FGFR2 ubiquitination to avoid its fate of lysosome degradation. Osteoblast conditional Otub1 knockout mice showed a bone loss, suggesting an important role of Fgfr2 in maintaining bone homeostasis ( Zhu et al, 2023b ).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of fibroblast growth factor receptor 2 in bone marrow mesenchymal stem cells enhances osteogenesis and promotes critical cranial bone defect regeneration

Zhou

Zhu

Shen

et al. 2023

Front. Cell Dev. Biol.

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Background: Reconstruction of cranial bone defects is one of the most challenging problems in reconstructive surgery, and several biological tissue engineering methods have been used to promote bone repair, such as genetic engineering of bone marrow mesenchymal stem cells (BMSCs). Fibroblast growth factor receptor 2 (Fgfr2) is an important regulator of bone construction and can be used as a potential gene editing site. However, its role in the osteogenesis process of BMSCs remains unclear. This article clarifies the function of Fgfr2 in BMSCs and explores the role of Fgfr2-overexpressed BMSCs carried by light-induced porous hydrogel (GelMA) in the repair of cranial bone defects.Methods: Lenti-virus was used to overexpress Fgfr2 in BMSCs, and cell counting kit-8, transwell, and flow cytometry assays were conducted to investigate the proliferation, migration, and characteristics. After 0, 3, 7, and 10 days of osteogenic or chondrogenic induction, the changes in osteogenic and chondrogenic ability were detected by real-time PCR, western blot, alkaline phosphatase staining, alizarin Red staining, and alcian blue staining. To investigate the viability of BMSCs carried by GelMA, calcein and propyl iodide staining were carried out as well. Finally, a critical cranial bone defect model was established in 6-week-old male mice and micro-computerized tomography, masson staining, and immunohistochemistry of OCN were conducted to test the bone regeneration properties of implanting Fgfr2-overexpressed BMSCs with GelMA in cranial bone defects over 6 weeks.Results: Overexpression of Fgfr2 in BMSCs significantly promoted cell proliferation and migration and increased the percentage of CD200+CD105+ cells. After osteogenic and chondrogenic induction, Fgfr2 overexpression enhanced both osteogenic and chondrogenic ability. Furthermore, in cranial bone defect regeneration, BMSCs carried by light-induced GelMA showed favorable biocompatibility, and Fgfr2-overexpressed BMSCs induced superior cranial bone regeneration compared to a normal BMSCs group and an untreated blank group.Conclusion:In vitro, Fgfr2 enhanced the proliferation, migration, and stemness of BMSCs and promoted osteogenesis and chondrogenesis after parallel induction. In vivo, BMSCs with Fgfr2 overexpression carried by GelMA showed favorable performance in treating critical cranial bone defects. This study clarifies the multiple functions of Fgfr2 in BMSCs and provides a new method for future tissue engineering.

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Section: Discussionmentioning

confidence: 99%

Overexpression of fibroblast growth factor receptor 2 in bone marrow mesenchymal stem cells enhances osteogenesis and promotes critical cranial bone defect regeneration

Zhou

Zhu

Shen

et al. 2023

Front. Cell Dev. Biol.

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“…The plasmid information of HOIP, HOIL-1, SHARPIN, SMURF1, SMADs and related mutants were described in the previous studies 2 , 62 . Potential HOIP-interacting proteins, such as HK1, HK2 were cloned into the 3 × Flag-CMV14 vectors.…”

Section: Methodsmentioning

confidence: 99%

“…Femurs from 8-week-old mice were fixed in 4% PFA for 48 h and then stored in 75% ethanol at 4 °C for Micro CT analysis according the previous study 62 and the femurs were subjected to a three-point bending test by using a universal testing device (CellScale Biomaterials Testing, Canada).…”

Section: Methodsmentioning

confidence: 99%

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Systematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis

Fu,

Li,

Zhang

et al. 2024

Nat Commun

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Linear ubiquitination catalyzed by HOIL-1-interacting protein (HOIP), the key component of the linear ubiquitination assembly complex, plays fundamental roles in tissue homeostasis by executing domain-specific regulatory functions. However, a proteome-wide analysis of the domain-specific interactome of HOIP across tissues is lacking. Here, we present a comprehensive mass spectrometry-based interactome profiling of four HOIP domains in nine mouse tissues. The interaction dataset provides a high-quality HOIP interactome resource with an average of approximately 90 interactors for each bait per tissue. HOIP tissue interactome presents a systematic understanding of linear ubiquitination functions in each tissue and also shows associations of tissue functions to genetic diseases. HOIP domain interactome characterizes a set of previously undefined linear ubiquitinated substrates and elucidates the cross-talk among HOIP domains in physiological and pathological processes. Moreover, we show that linear ubiquitination of Integrin-linked protein kinase (ILK) decreases focal adhesion formation and promotes the detachment of Shigella flexneri-infected cells. Meanwhile, Hoip deficiency decreases the linear ubiquitination of Smad ubiquitination regulatory factor 1 (SMURF1) and enhances its E3 activity, finally causing a reduced bone mass phenotype in mice. Overall, our work expands the knowledge of HOIP-interacting proteins and provides a platform for further discovery of linear ubiquitination functions in tissue homeostasis.

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“…Data suggest that this is a result of an increased proliferation of parenchymal and mesenchymal cells which leads to a reduction in saccular air space, potentially elevating lung tissue resistant to mechanical stretching ( Ruiz-Serrano et al, 2021 ). Furthermore, it has also been demonstrated that OTUB1 deficient mice exhibit a significant delay in bone formation in the skull and limbs at embryonic day E16.5 when compared to control littermates, which becomes even more pronounced at E18.5 ( Zhu et al, 2023 ). In adult mice, deletion of Otub1 also induces proliferation in lung tissue and alveolar hyperventilation.…”

Section: Non-catalytic Functions Of Dubs and Ubl Proteasesmentioning

confidence: 99%

In the moonlight: non-catalytic functions of ubiquitin and ubiquitin-like proteases

Campos Alonso,

Knobeloch

2024

Front. Mol. Biosci.

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Proteases that cleave ubiquitin or ubiquitin-like proteins (UBLs) are critical players in maintaining the homeostasis of the organism. Concordantly, their dysregulation has been directly linked to various diseases, including cancer, neurodegeneration, developmental aberrations, cardiac disorders and inflammation. Given their potential as novel therapeutic targets, it is essential to fully understand their mechanisms of action. Traditionally, observed effects resulting from deficiencies in deubiquitinases (DUBs) and UBL proteases have often been attributed to the misregulation of substrate modification by ubiquitin or UBLs. Therefore, much research has focused on understanding the catalytic activities of these proteins. However, this view has overlooked the possibility that DUBs and UBL proteases might also have significant non-catalytic functions, which are more prevalent than previously believed and urgently require further investigation. Moreover, multiple examples have shown that either selective loss of only the protease activity or complete absence of these proteins can have different functional and physiological consequences. Furthermore, DUBs and UBL proteases have been shown to often contain domains or binding motifs that not only modulate their catalytic activity but can also mediate entirely different functions. This review aims to shed light on the non-catalytic, moonlighting functions of DUBs and UBL proteases, which extend beyond the hydrolysis of ubiquitin and UBL chains and are just beginning to emerge.

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OTUB1 promotes osteoblastic bone formation through stabilizing FGFR2

Cited by 18 publications

References 58 publications

Overexpression of fibroblast growth factor receptor 2 in bone marrow mesenchymal stem cells enhances osteogenesis and promotes critical cranial bone defect regeneration

Overexpression of fibroblast growth factor receptor 2 in bone marrow mesenchymal stem cells enhances osteogenesis and promotes critical cranial bone defect regeneration

Systematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis

In the moonlight: non-catalytic functions of ubiquitin and ubiquitin-like proteases

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