CHIP inhibits odontoblast differentiation through promoting DLX3 polyubiquitylation and degradation

Author:

Zheng Huiwen123,Zhang Xiaobo12,Fu Jing12,Xue Yifan12,Chen Zhi1,Yang Guobin1,Chen YiPing4,Chen Di5,Yuan Guohua12ORCID

Affiliation:

1. The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University 1 , Wuhan 430079, China

2. Frontier Science Center for Immunology and Metabolism, Wuhan University 2 , Wuhan 430071, China

3. Pediatric Dentistry, Nanjing Stomatology Hospital, Medical School of Nanjing University 3 , No 30 Zhongyang Road, Nanjing 210008 , China

4. Tulane University 4 Department of Cell and Molecular Biology , , New Orleans, LA 70118, USA

5. Research Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences 5 , Shenzhen 518055 , China

Abstract

ABSTRACT 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.

Funder

National Natural Science Foundation of China

Publisher

The Company of Biologists

Subject

Developmental Biology,Molecular Biology

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