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Heterokaryon Technique for Analysis of Cell Type-specific Localization
Published on: March 11, 2011
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p37 regulates VCP/p97 shuttling and functions in the nucleus and cytosol
Lidia Wrobel1,2, Johanna L Hoffmann1,2, Xinyi Li1,2
1Department of Medical Genetics, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
Science Advances
|May 3, 2024
Summary
The protein valosin-containing protein (VCP) shuttles between the cytosol and nucleus, regulated by p37. This VCP-p37 interaction impacts DNA repair and autophagy, with implications for proteinopathies.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Valosin-containing protein (VCP), an AAA+-ATPase, is crucial for protein homeostasis and cellular functions.
- VCP localizes to various subcellular compartments, but the regulation of its nucleocytoplasmic distribution remains unclear.
Purpose of the Study:
- To identify factors regulating VCP's movement between the cytosol and nucleus.
- To understand the functional significance of VCP's subcellular localization.
- To investigate the role of VCP-p37 interaction in disease.
Main Methods:
- Protein interaction studies
- Cellular localization assays
- DNA damage response assays
- Genetic manipulation of p37 levels
Main Results:
- p37 (UBXN2B) was identified as a key regulator of VCP nucleocytoplasmic shuttling.
- p37-dependent VCP localization is essential for both cytosolic (autophagy) and nuclear (DNA repair) functions.
- Mutations in VCP associated with multisystem proteinopathy increase p37 binding, impairing nuclear VCP import and increasing DNA damage susceptibility.
- Reducing p37 levels restored VCP localization and DNA damage resistance in cells with VCP mutations.
Conclusions:
- p37 acts as a critical mediator controlling VCP's subcellular distribution and function.
- Dysregulation of the VCP-p37 interaction contributes to disease pathogenesis by affecting DNA repair.
- Targeting the VCP-p37 axis offers a potential therapeutic strategy for VCP-associated proteinopathies.
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