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In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
Published on: July 25, 2019
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CARPs regulate STUB1 and its pathogenic mutants aggregation kinetics by mono-ubiquitination
Rahul Sharma1, Prema Mondal1, Srinivasa M Srinivasula1
1School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, India.
The FEBS Journal
|February 28, 2023
Summary
CARP2, a ubiquitin ligase, regulates STIP1 Homologous and U-Box-containing protein 1 (STUB1) by promoting its aggregation. This finding reveals CARP proteins as key regulators of STUB1 dynamics in neurodegenerative diseases.
Area of Science:
- Neuroscience
- Molecular Biology
- Protein Biochemistry
Background:
- Protein aggregates like alpha-synuclein and tau are implicated in neurodegenerative diseases such as Parkinson's and Alzheimer's.
- STIP1 Homologous and U-Box-containing protein 1 (STUB1) is crucial for proteostasis and insulin signaling, with mutations linked to spinocerebellar ataxia 16 (SCAR16).
- Mechanisms controlling STUB1 aggregate assembly, despite its neuroprotective role, remain largely unknown.
Purpose of the Study:
- To identify novel regulators of STUB1 aggregate assembly.
- To elucidate the role of CARP2 in STUB1 dynamics.
- To investigate the impact of CARP2-mediated modification on STUB1.
Main Methods:
- Co-immunoprecipitation to assess protein interactions.
- Ubiquitination assays to determine CARP2's enzymatic activity on STUB1.
- Biochemical assays to analyze STUB1 aggregate formation and solubility.
- Comparison of wild-type and mutant STUB1 behavior.
Main Results:
- CARP2 directly interacts with and mono-ubiquitinates STUB1.
- CARP2 regulates STUB1 via its TPR motif, which also interacts with HSP70.
- CARP2-mediated modification induces the formation of detergent-insoluble STUB1 aggregates.
- Pathogenic STUB1 mutants exhibit increased susceptibility to CARP2-induced aggregation compared to wild-type STUB1.
Conclusions:
- CARP2 is identified as a novel regulator of STUB1.
- CARP proteins (CARP1 & CARP2) are novel regulators controlling STUB1's cytosolic and aggregate dynamics.
- Understanding CARP2-STUB1 interaction offers insights into neurodegenerative disease mechanisms.
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