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Updated: Aug 24, 2025
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Analysis of SCAP N-glycosylation and Trafficking in Human Cells
Published on: November 8, 2016
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A multienzyme S-nitrosylation cascade regulates cholesterol homeostasis
Colin T Stomberski1, Nicholas M Venetos1, Hua-Lin Zhou2
1Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44016, USA; Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Cell Reports
|October 26, 2022
Summary
Mice lacking the denitrosylase SCoR2 show lower cholesterol levels. This is due to reduced secretion of PCSK9, a key protein regulating cholesterol, revealing a new pathway for cardiovascular disease treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Science
Background:
- Protein S-nitrosylation is enzymatically controlled by specific nitrosylases and denitrosylases.
- Understanding these enzymes is crucial for regulating protein function and cellular processes.
Purpose of the Study:
- To investigate the role of the denitrosylase SCoR2 (S-nitroso-Coenzyme A Reductase 2) in regulating cholesterol metabolism.
- To elucidate the molecular mechanisms by which SCoR2 influences PCSK9 secretion and cholesterol levels.
Main Methods:
- Utilized SCoR2-deficient mice to study cholesterol levels and PCSK9 secretion.
- Investigated protein-protein interactions within the endoplasmic reticulum (ER) secretory machinery.
- Analyzed the S-nitrosylation and denitrosylation cascade involving SAR1, SURF4, and PCSK9.
Main Results:
- SCoR2 deficiency in mice led to significantly reduced serum cholesterol.
- Reduced PCSK9 secretion was observed in SCoR2-deficient mice.
- Identified SAR1 and SURF4 as S-nitrosylases and SCoR2 as a denitrosylase controlling PCSK9 secretion via S-nitrosylation.
Conclusions:
- Enzymatic control of cholesterol levels involves S-nitrosylation of PCSK9 by SAR1/SURF4, counteracted by SCoR2-mediated denitrosylation.
- Targeting SCoR2 or the identified S-nitrosylation pathway offers a novel therapeutic strategy for cardiovascular diseases.
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