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조회566

한양대학교 의과대학

Cell Death Differ., Published 10 March 2022 | https://doi.org/10.1038/s41418-022-00956-7 Genome-wide screening for deubiquitinase subfamily identifies ubiquitin-specific protease 49 as a novel regulator of odontogenesis

Kamini Kaushal^1,5, Eun-Jung Kim^2,5, Apoorvi Tyagi^1,5, Janardhan Keshav Karapurkar¹, Saba Haq³, Han-Sung Jung^2,*, Kye-Seong Kim^1,4,* and Suresh Ramakrishna^1,4,*

¹Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, South Korea. ²Division in Anatomy and Developmental Biology, Department of Oral Biology, Taste Research Center, Oral Science Research Center, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul 03722, South Korea. ³Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 04763, South Korea. ⁴College of Medicine, Hanyang University, Seoul 04763, South Korea. ⁵These authors contributed equally: Kamini Kaushal, Eun-Jung Kim, Apoorvi Tyagi.

^*Corresponding author.

Abstract

Proteins expressed by the paired box gene 9 (PAX9) and Msh Homeobox 1 (MSX1) are intimately involved in tooth development (odontogenesis). The regulation of PAX9 and MSX1 protein turnover by deubiquitinating enzymes (DUBs) plausibly maintain the required levels of PAX9 and MSX1 during odontogenesis. Herein, we used a loss-of-function CRISPR-Cas9-mediated DUB KO library kit to screen for DUBs that regulate PAX9 and MSX1 protein levels. We identify and demonstrate that USP49 interacts with and deubiquitinates PAX9 and MSX1, thereby extending their protein half-lives. On the other hand, the loss of USP49 reduces the levels of PAX9 and MSX1 proteins, which causes transient retardation of odontogenic differentiation in human dental pulp stem cells and delays the differentiation of human pluripotent stem cells into the neural crest cell lineage. USP49 depletion produced several morphological defects during tooth development, such as reduced dentin growth with shrunken enamel space, and abnormal enamel formation including irregular mineralization. In sum, our results suggest that deubiquitination of PAX9 and MSX1 by USP49 stabilizes their protein levels to facilitate successful odontogenesis.

논문정보

형식Research article
게재일2022년 03월 (BRIC 등록일 2022-05-26)
연구진국내 연구진
분야 생명과학 > 유전자발현

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