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Lanosterol modulates proteostasis via dissolving cytosolic sequestosomes/aggresome-like induced structures.
Li-Dan Hu1, Jing Wang1, Xiang-Jun Chen2
1State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Biochimica Et Biophysica Acta. Molecular Cell Research
|December 1, 2019
Summary
Lanosterol effectively dissolves protein aggregates, aiding cellular proteostasis. This small molecule, unlike cholesterol, helps cells clear misfolded proteins by working with heat shock proteins.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Protein aggregation into sequestosomes/ALIS is crucial for proteostasis.
- p62/SQSTM1 sequesters ubiquitinated proteins, but disaggregase mechanisms remain unclear.
Purpose of the Study:
- Investigate lanosterol's role in protein aggregate dissolution.
- Identify novel regulators of proteostasis beyond protein modulators.
Main Methods:
- Utilized HeLa and HEK-293A cell lines under stressed and non-stressed conditions.
- Assessed sequestosome/ALIS/aggresome formation and protein release.
- Measured proteasome and autophagic activity, HSF1 activation, and heat shock protein expression.
Main Results:
- Lanosterol significantly reduced sequestosome/ALIS/aggresome size and number.
- Lanosterol released trapped proteins without affecting proteasome or autophagy.
- Lanosterol activated HSF1 and upregulated heat shock proteins, unlike cholesterol.
Conclusions:
- Lanosterol acts as a disaggregase, facilitating protein aggregate clearance.
- Coordinated action of lanosterol disaggregation and heat shock protein refolding aids protein recycling.
- Endogenous low-molecular-weight compounds like lanosterol are key proteostasis regulators.
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