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UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome
Roland Hjerpe1, John S Bett1, Matthew J Keuss2
1Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, Davidson Building, Henry Wellcome Lab of Cell Biology, University of Glasgow, G12 8QQ Glasgow, UK; The MRC Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland.
Cell
|August 2, 2016
Summary
Protein clearance is vital for cell survival. A new pathway uses UBQLN2 and HSP70 to remove protein aggregates via the proteasome, with mutations causing neurodegeneration.
Area of Science:
- Cellular biology
- Molecular mechanisms of protein degradation
- Neuroscience
Background:
- Protein homeostasis is crucial for cell survival.
- Misfolded and aggregated proteins can be toxic.
- The 26S proteasome degrades ubiquitylated proteins, but other pathways exist.
Purpose of the Study:
- To investigate the role of proteasome shuttle factors in protein aggregate clearance.
- To elucidate the mechanism by which UBQLN2 contributes to protein homeostasis.
- To understand the link between UBQLN2 dysfunction and neurodegeneration.
Main Methods:
- Investigated the interaction between UBQLN2, HSP70, and the 26S proteasome.
- Examined protein aggregate clearance in cellular models.
- Assessed the impact of UBQLN2 mutations on chaperone binding and aggregate clearance.
- Studied cognitive deficits in mouse models with UBQLN2 mutations.
Main Results:
- UBQLN2 acts with HSP70-HSP110 disaggregase machinery to clear protein aggregates via the 26S proteasome.
- UBQLN2 recognizes client-bound HSP70 and facilitates protein degradation.
- This nuclear clearance pathway is distinct from autophagy.
- Human UBQLN2 mutations impair chaperone binding, aggregate clearance, and cause cognitive deficits in mice.
Conclusions:
- UBQLN2 mediates a novel pathway for clearing protein aggregates in the nucleus.
- Dysfunction of this UBQLN2-mediated pathway contributes to neurodegenerative diseases.
- Targeting this pathway may offer therapeutic strategies for neurodegeneration.
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