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Chaperone-Mediated Protein Disaggregation Triggers Proteolytic Clearance of Intra-nuclear Protein Inclusions
Fabian den Brave1, Lucas V Cairo2, Chandhuru Jagadeesan2
1Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
Cell Reports
|June 4, 2020
Summary
A novel nuclear pathway involving Apj1 and Hsp70 disaggregates toxic protein inclusions, promoting their clearance by the 26S proteasome and preventing neurodegenerative disease pathology.
Area of Science:
- Cell Biology
- Neuroscience
- Protein Homeostasis
Background:
- Insoluble protein inclusions in the nucleus and cytosol impair protein homeostasis.
- Nuclear protein aggregates require solubilization before 26S proteasome degradation due to the lack of autophagy.
- This is a hallmark of neurodegenerative diseases.
Purpose of the Study:
- To identify a nuclear protein quality control pathway for aggregate clearance.
- To investigate the role of the nuclear J-domain protein Apj1 in aggregate disaggregation and turnover.
Main Methods:
- Yeast models were used to study protein aggregate formation and clearance.
- Investigated the interaction of Apj1 with Hsp70 and Hsp104.
- Assessed the impact of Apj1 activity on protein turnover and the accumulation of toxic species.
Main Results:
- Apj1, with Hsp70, disaggregates nuclear protein aggregates independently of Hsp104.
- This Apj1/Hsp70-mediated disaggregation promotes protein turnover rather than refolding.
- Loss of Apj1 leads to the accumulation of soluble toxic protein species.
Conclusions:
- A nuclear protein quality control pathway involving Apj1/Hsp70 facilitates the clearance of toxic nuclear inclusions.
- This system coordinates with the 26S proteasome for efficient removal of aggregated proteins.
- This pathway is crucial for maintaining nuclear protein homeostasis and preventing neurotoxicity.
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