多酶 S-亚硝基化级联反应调节胆固醇稳态。
A multienzyme S-nitrosylation cascade regulates cholesterol homeostasis.
机构信息
Department 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.
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; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44016, USA.
出版信息
Cell Rep. 2022 Oct 25;41(4):111538. doi: 10.1016/j.celrep.2022.111538.
Accumulating evidence suggests that protein S-nitrosylation is enzymatically regulated and that specificity in S-nitrosylation derives from dedicated S-nitrosylases and denitrosylases that conjugate and remove S-nitrosothiols, respectively. Here, we report that mice deficient in the protein denitrosylase SCoR2 (S-nitroso-Coenzyme A Reductase 2; AKR1A1) exhibit marked reductions in serum cholesterol due to reduced secretion of the cholesterol-regulating protein PCSK9. SCoR2 associates with endoplasmic reticulum (ER) secretory machinery to control an S-nitrosylation cascade involving ER cargo-selection proteins SAR1 and SURF4, which moonlight as S-nitrosylases. SAR1 acts as a SURF4 nitrosylase and SURF4 as a PCSK9 nitrosylase to inhibit PCSK9 secretion, while SCoR2 counteracts nitrosylase activity by promoting PCSK9 denitrosylation. Inhibition of PCSK9 by an NO-based drug requires nitrosylase activity, and small-molecule inhibition of SCoR2 phenocopies the PCSK9-mediated reductions in cholesterol observed in SCoR2-deficient mice. Our results reveal enzymatic machinery controlling cholesterol levels through S-nitrosylation and suggest a distinct treatment paradigm for cardiovascular disease.
越来越多的证据表明，蛋白质的 S-亚硝基化是受酶调控的，S-亚硝基化的特异性来源于专门的 S-亚硝基转移酶和 S-硝基还原酶，它们分别将 S-亚硝基硫醇结合和去除。在这里，我们报告说，缺乏蛋白质硝基还原酶 SCoR2（S-亚硝基辅酶 A 还原酶 2；AKR1A1）的小鼠由于调节胆固醇的蛋白质 PCSK9 分泌减少，导致血清胆固醇明显降低。SCoR2 与内质网（ER）分泌机制结合，控制涉及 ER 货物选择蛋白 SAR1 和 SURF4 的 S-亚硝基化级联反应，SAR1 和 SURF4 作为 S-亚硝基转移酶兼职。SAR1 作为 SURF4 的硝基转移酶，SURF4 作为 PCSK9 的硝基转移酶，抑制 PCSK9 的分泌，而 SCoR2 通过促进 PCSK9 的脱硝基化来抵消硝基转移酶的活性。基于 NO 的药物抑制 PCSK9 需要硝基转移酶活性，小分子抑制 SCoR2 模拟了在 SCoR2 缺陷型小鼠中观察到的 PCSK9 介导的胆固醇降低。我们的研究结果揭示了通过 S-亚硝基化控制胆固醇水平的酶学机制，并为心血管疾病提供了一种独特的治疗模式。
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