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

doi:10.1073/pnas.1620306114

Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability

Proc Natl Acad Sci U S A. 2017 May 2;114(18):4691-4696. doi: 10.1073/pnas.1620306114. Epub 2017 Apr 17.

Authors

Affiliations

¹ Department of Life Science, University of Seoul, Seoul 130-743, Republic of Korea.
² Department of Mathematics, University of Seoul, Seoul 130-743, Republic of Korea.
³ Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
⁴ Department of Gastroenterology and Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea.
⁵ Department of Life Science, University of Seoul, Seoul 130-743, Republic of Korea; ej70@uos.ac.kr.

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-activity-dependent 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.

Keywords: Hippo signaling; ITCH; YOD1; cell density; deubiquitinase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Endopeptidases / genetics
Endopeptidases / metabolism*
HEK293 Cells
HeLa Cells
Hepatocytes / metabolism*
Hepatocytes / pathology
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Liver Neoplasms / genetics
Liver Neoplasms / metabolism*
Liver Neoplasms / pathology
Mice
Mice, Transgenic
MicroRNAs / genetics
MicroRNAs / metabolism
NIH 3T3 Cells
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Protein Stability
RNA, Neoplasm / genetics
RNA, Neoplasm / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Thiolester Hydrolases / genetics
Thiolester Hydrolases / metabolism*
Trans-Activators
Transcription Factors
Transcriptional Coactivator with PDZ-Binding Motif Proteins
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*

Substances

Adaptor Proteins, Signal Transducing
Intracellular Signaling Peptides and Proteins
MIRN21 microRNA, human
MIRN21 microRNA, mouse
MicroRNAs
Neoplasm Proteins
RNA, Neoplasm
Repressor Proteins
Trans-Activators
Transcription Factors
Transcriptional Coactivator with PDZ-Binding Motif Proteins
WWTR1 protein, human
Wwtr1 protein, mouse
ITCH protein, human
Itch protein, mouse
Ubiquitin-Protein Ligases
YOD1 protein, human
Thiolester Hydrolases
Endopeptidases