Genome-wide screening for deubiquitinase subfamily identifies ubiquitin-specific protease 49 as a novel regulator of odontogenesis.

Autor: Kaushal K; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea., Kim EJ; Division 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., Tyagi A; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea., Karapurkar JK; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea., Haq S; Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, 04763, South Korea., Jung HS; Division 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. hsj8076@gmail.com., Kim KS; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea. ks66kim@hanyang.ac.kr.; College of Medicine, Hanyang University, Seoul, 04763, South Korea. ks66kim@hanyang.ac.kr., Ramakrishna S; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea. suresh.ramakris@gmail.com.; College of Medicine, Hanyang University, Seoul, 04763, South Korea. suresh.ramakris@gmail.com.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2022 Sep; Vol. 29 (9), pp. 1689-1704. Date of Electronic Publication: 2022 Mar 10.
DOI: 10.1038/s41418-022-00956-7
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz: