PNAS(Proceedings of the National Academy of Sciences of the United States of America), 2017, 01, 4691─4696, DOI: https://doi.org/10.1073/pnas.1620306114

Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability

Youngeun Kima, Yonghee Song; Jeong-Rae Kim; Kyungjoo Cho; Hyuk Moon; Simon Weonsang Ro; Eunjeong Seo; Yeon-Mi Ryu; Seung-Jae Myung; Eek-Hoon Jhoa

Abstract

Hippo signaling controls the expression of genes regulating cell proliferation and survival and organ size. The regulation of core components in the Hippo pathway by phosphorylation has been extensively investigated, but the roles of ubiquitination？deubiquitination processes are largely unknown. To identify deubiquitinase(s) that regulates Hippo signaling, we performed unbiased siRNA screening and found that YOD1 controls biological responses mediated by YAP/TAZ. Mechanistically, YOD1 deubiquitinates ITCH, an E3 ligase of LATS, and enhances the stability of ITCH, which leads to reduced levels of LATS and a subsequent increase in the YAP/TAZ level. Furthermore, we show that the miR-21-mediated regulation of YOD1 is responsible for the cell-density-dependent changes in YAP/TAZ levels. Using a transgenic mouse model, we demonstrate that the inducible expression of YOD1 enhances the proliferation of hepatocytes and leads to hepatomegaly in a YAP/TAZ-activitydependent manner.
Moreover, we find a strong correlation between YOD1 and YAP expression in liver cancer patients. Overall, our data strongly suggest that YOD1 is a regulator of the Hippo pathway and would be a therapeutic target to treat liver cancer.

• DOI: https://doi.org/10.1073/pnas.1620306114
• ISBN or ISSN: 0027-8424

• 본 연구는 질병관리본부 연구개발과제(과제번호 2017-보건의료생물자원종합관리) 연구비를 지원받아 수행되었습니다.
• This research was supported by a fund(code 2017-보건의료생물자원종합관리) by Research of Korea Centers for Disease Control and Prevention.