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USP2 mediates HDAC6-dependent stabilization of HIPK2 and enhances its proapoptotic function
Hye-Ji Lee1, Jeong Yoon Park1, Hana Im1
1Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, 05006, Republic of Korea.
Biochemical and Biophysical Research Communications
|July 17, 2026
Summary
The deubiquitinase USP2 stabilizes HIPK2 protein by interacting with HDAC6. This interaction enhances HIPK2
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- HIPK2 (HIP11-interacting protein kinase 2) is a nuclear kinase involved in development and cellular stress responses, including DNA damage.
- HDAC6 (Histone Deacetylase 6) was previously shown to increase HIPK2 protein stability through its UBP domain, independent of its deacetylase activity.
Purpose of the Study:
- To identify the deubiquitinase responsible for stabilizing HIPK2.
- To elucidate the mechanism by which HDAC6 regulates HIPK2 stability.
- To investigate the functional consequences of USP2-mediated HIPK2 stabilization.
Main Methods:
- Cell-based assays to assess protein stability and ubiquitination.
- Co-immunoprecipitation to detect protein complex formation.
- Knockdown and chemical inhibition of USP2 and HDAC6.
- Analysis of TNFα-induced cell death.
Main Results:
- USP2 (Ubiquitin-specific protease 2) was identified as a deubiquitinase that stabilizes HIPK2.
- USP2 forms a complex with HDAC6 and HIPK2, and this interaction is crucial for HDAC6-mediated HIPK2 stabilization.
- USP2 knockdown or inhibition decreased HIPK2 protein levels and polyubiquitination.
- USP2-mediated stabilization of HIPK2 enhanced TNFα-induced apoptosis.
Conclusions:
- USP2 deubiquitinates and stabilizes HIPK2 protein, likely by complexing with HDAC6.
- The regulation of HIPK2 stability by HDAC6 is dependent on USP2 activity.
- USP2 enhances the proapoptotic function of HIPK2.
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