A WWP2–PTEN–KLF5 signaling axis regulates odontoblast differentiation and dentinogenesis in mice

Fu, Jing; Zhang, Xiaobo; Zheng, Huiwen; Yang, Guobin; Chen, Zhi; Yuan, Guohua

doi:10.1016/j.jbc.2022.102220

Cited by 9 publications

(7 citation statements)

References 43 publications

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“…Ubiquitylation is an important form of post-translational modifications and influences a variety of developmental events. Several ubiquitin ligases have been identified to be involved in tooth development (Fu et al, 2022(Fu et al, , 2021Lee et al, 2011;Zheng et al, 2020). CHIP is an E3 ubiquitin ligase that plays crucial roles in various physiological and pathological processes through regulating the stability of substrate proteins (Cao et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

CHIP inhibits odontoblast differentiation through promoting DLX3 polyubiquitylation and degradation

Zheng

Zhang

et al. 2023

Development

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Dentin is the major hard tissue of teeth formed by differentiated odontoblasts. How odontoblast differentiation is regulated remains enigmatic. Here, we report that the E3 ubiquitin ligase CHIP is highly expressed in undifferentiated dental mesenchymal cells and downregulated after differentiation of odontoblasts. Ectopic expression of CHIP inhibits odontoblastic differentiation of mouse dental papilla cells, whereas knockdown of endogenous CHIP has opposite effects. Chip (Stub1) knockout mice display increased formation of dentin and enhanced expression of odontoblast differentiation markers. Mechanistically, CHIP interacts with and induces K63 polyubiquitylation of the transcription factor DLX3, leading to its proteasomal degradation. Knockdown of DLX3 reverses the enhanced odontoblastic differentiation caused by knockdown of CHIP. These results suggest that CHIP inhibits odontoblast differentiation by targeting its tooth-specific substrate DLX3. Furthermore, our results indicate that CHIP competes with another E3 ubiquitin ligase, MDM2, that promotes odontoblast differentiation by monoubiquitylating DLX3. Our findings suggest that the two E3 ubiquitin ligases CHIP and MDM2 reciprocally regulate DLX3 activity by catalyzing distinct types of ubiquitylation, and reveal an important mechanism by which differentiation of odontoblasts is delicately regulated by divergent post-translational modifications.

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Section: Discussionmentioning

confidence: 99%

CHIP inhibits odontoblast differentiation through promoting DLX3 polyubiquitylation and degradation

Zheng

Zhang

et al. 2023

Development

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“…There is no literature reporting a link between these two miRNAs and dentinogenesis per se, but we can assume that their respective impact on the PTEN and BMP6 pathways may be responsible for dysregulation of dentinogenesis. [65][66][67] The miRNAs let-7g-5p and miR-15b-5p are less known in bone. Some studies suggest that let-7g-5p may participate in osteoblastic differentiation, but the mechanisms are not yet well understood, with a more oncogenic role in extraosseous bone.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dysregulation of MicroRNAs in Adult Osteogenesis Imperfecta: The miROI Study

Mercier-Guery,

Millet,

Merle

et al. 2023

Journal of Bone and Mineral Research

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As epigenetic regulators of gene expression, circulating microRNAs (miRNAs) have been described in several bone diseases as potential prognostic markers. The aim of our study was to identify circulating miRNAs potentially associated with the severity of Osteogenesis Imperfecta (OI), in 3 steps. We have screened by RNA sequencing for the microRNAs (miRNAs) that were differentially expressed in sera of a small group of OI patients versus controls and then conducted a validation phase by RT‐qPCR analysis of sera of a larger patient population. In the first phase of miROI, we found 79 miRNAs that were significantly differentially expressed. We therefore selected 19 of them as the most relevant. In the second phase, we were able to validate the significant overexpression of 8 miRNAs in the larger OI group. Finally, we looked for a relationship between the level of variation of the validated miRNAs and the clinical characteristics of OI. We found a significant difference in the expression of two microRNAs in those patients with Dentinogenesis Imperfecta. After reviewing the literature, we found 6 of the 8 miRNAs already known to have a direct action on bone homeostasis. Furthermore, the use of a miRNA‐gene interaction prediction model revealed a 100% probability of interaction between 2 of the 8 confirmed miRNAs and COL1A1 and/or COL1A2. This is the first study to establish the miRNA signature in OI, showing a significant modification of miRNAs expression potentially involved in the regulation of genes involved in the physiopathology of OI.This article is protected by copyright. All rights reserved.

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“…A study verified that WWP2, which is more involved in substrate mono-ubiquitination, could promote odontoblastic differentiation of mDPCs through WWP2-mediated KLF5 mono-ubiquitination in the nucleus, and that the PPPSY (PY2) motif of KLF5 and cysteine 838 (Cys838) of WWP2 were crucial for WWP2-mediated KLF5 transactivation [ 137 ]. Moreover, the in vivo promotive role of WWP2 in dentinogenesis was identified in WWP2 knockout mice [ 138 ]. In addition, the results demonstrated that PTEN was targeted by WWP2 for ubiquitination degradation, and its inhibitory effect on the transcriptional activity of KLF5 was suppressed by WWP2.…”

Section: Nedd4 E3 Ligases and Toothmentioning

confidence: 99%

“…In addition, the results demonstrated that PTEN was targeted by WWP2 for ubiquitination degradation, and its inhibitory effect on the transcriptional activity of KLF5 was suppressed by WWP2. [ 138 ].…”

Section: Nedd4 E3 Ligases and Toothmentioning

confidence: 99%

NEDD4 E3 Ligases: Functions and Mechanisms in Bone and Tooth

Chu

Liu

et al. 2022

IJMS

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Protein ubiquitination is a precisely controlled enzymatic cascade reaction belonging to the post-translational modification of proteins. In this process, E3 ligases catalyze the binding of ubiquitin (Ub) to protein substrates and define specificity. The neuronally expressed developmentally down-regulated 4 (NEDD4) subfamily, belonging to the homology to E6APC terminus (HECT) class of E3 ligases, has recently emerged as an essential determinant of multiple cellular processes in different tissues, including bone and tooth. Here, we place special emphasis on the regulatory role of the NEDD4 subfamily in the molecular and cell biology of osteogenesis. We elucidate in detail the specific roles, downstream substrates, and upstream regulatory mechanisms of the NEDD4 subfamily. Further, we provide an overview of the involvement of E3 ligases and deubiquitinases in the development, repair, and regeneration of another mineralized tissue—tooth.

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A WWP2–PTEN–KLF5 signaling axis regulates odontoblast differentiation and dentinogenesis in mice

Cited by 9 publications

References 43 publications

CHIP inhibits odontoblast differentiation through promoting DLX3 polyubiquitylation and degradation

CHIP inhibits odontoblast differentiation through promoting DLX3 polyubiquitylation and degradation

Dysregulation of MicroRNAs in Adult Osteogenesis Imperfecta: The miROI Study

NEDD4 E3 Ligases: Functions and Mechanisms in Bone and Tooth

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