Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability

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

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4691-4696
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number18
DOIs
Publication statusPublished - 2 May 2017

Keywords

  • Cell density
  • Deubiquitinase
  • Hippo signaling
  • ITCH
  • YOD1

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