Organ defects of the Usp7K444R mutant mouse strain indicate the essential role of K63-polyubiquitinated Usp7 in organ formation

Han Tsang Wu, Yueh Te Lin, Shan Hwu Chew, Kou Juey Wu*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

1 Scopus citations


Background: K63-linked polyubiquitination of proteins have nonproteolytic functions and regulate the activity of many signal transduction pathways. USP7, a HIF1α deubiquitinase, undergoes K63-linked polyubiquitination under hypoxia. K63-polyubiquitinated USP7 serves as a scaffold to anchor HIF1α, CREBBP, the mediator complex, and the super elongation complex to enhance HIF1α-induced gene transcription. However, the physiological role of K63-polyubiquitinated USP7 remains unknown. Methods: Using a Usp7K444R point mutation knock-in mouse strain, we performed immunohistochemistry and standard molecular biological methods to examine the organ defects of liver and kidney in this knock-in mouse strain. Mechanistic studies were performed by using deubiquitination, immunoprecipitation, and quantitative immunoprecipitations (qChIP) assays. Results: We observed multiple organ defects, including decreased liver and muscle weight, decreased tibia/fibula length, liver glycogen storage defect, and polycystic kidneys. The underlying mechanisms include the regulation of protein stability and/or modulation of transcriptional activation of several key factors, leading to decreased protein levels of Prr5l, Hnf4α, Cebpα, and Hnf1β. Repression of these crucial factors leads to the organ defects described above. Conclusions: K63-polyubiquitinated Usp7 plays an essential role in the development of multiple organs and illustrates the importance of the process of K63-linked polyubiquitination in regulating critical protein functions.

Original languageEnglish
Pages (from-to)122-133
Number of pages12
JournalBiomedical Journal
Issue number1
StatePublished - 02 2023

Bibliographical note

Copyright © 2022 Chang Gung University. Published by Elsevier B.V. All rights reserved.


  • Glycogen storage
  • K63-linked polyubiquitination
  • Knock-in mouse
  • Polycystic kidney
  • Usp7
  • Ubiquitination
  • Animals
  • Signal Transduction
  • Mice, Mutant Strains
  • Ubiquitin-Specific Peptidase 7/genetics
  • Mice
  • Kidney/metabolism


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