This article reviews the discovery of PCSK9, its structure-function characteristics, and its presently known and proposed novel biological functions. The major critical function of PCSK9 deduced from human and mouse studies, as well as cellular and structural analyses, is its role in increasing the levels of circulating LDL-cholesterol (LDLc), via its ability to enhance the sorting and escort of the cell surface LDL receptor (LDLR) to lysosomes. This implicates the binding of the catalytic domain of PCSK9 to the EGF-A domain of the LDLR. This also requires the presence of the C-terminal Cys/His-rich domain (CHRD), its binding to the secreted cytosolic cyclase associated protein 1 (CAP-1), and possibly another membrane-bound “protein X”. Curiously, in PCSK9-deficient mice, an alternative to the downregulation of the surface levels of the LDLR by PCSK9 is taking place in the liver of female mice in a 17β-estradiol-dependent manner by still an unknown mechanism. Recent studies have extended our understanding of the biological functions of PCSK9, namely its implication in septic shock, vascular inflammation, viral infections (Dengue; SARS-CoV-2) or immune checkpoint modulation in cancer via the regulation of the cell surface levels of the T-cell receptor and MHC-I, which govern the anti-tumoral activity of CD8 ⁺ T cells. Because PCSK9 inhibition may be advantageous in these processes, the availability of injectable safe PCSK9 inhibitors (PCSK9i) that reduces by 50-60% LDLc above the effect of statins is highly valuable. Indeed, injectable PCSK9 mAb or siRNA could be added to current immunotherapies in cancer/metastasis.

中文翻译：

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PCSK9 的多面生物学

本文回顾了 PCSK9 的发现、其结构-功能特征以及目前已知和提出的新生物学功能。从人类和小鼠研究以及细胞和结构分析中推断出的 PCSK9 的主要关键功能是它在提高循环低密度脂蛋白胆固醇 (LDLc) 水平方面的作用，通过其增强细胞表面低密度脂蛋白受体 (LDLR) 分选和护送至溶酶体的能力。这暗示了 PCSK9 的催化结构域与 LDLR 的 EGF-A 结构域的结合。这还需要 C 末端 Cys/His 富集域 (CHRD) 的存在，它与分泌的胞质环化酶相关蛋白 1 (CAP-1) 以及可能的另一种膜结合“蛋白 X”的结合。奇怪的是，在 PCSK9 缺陷小鼠中，PCSK9 对 LDLR 表面水平下调的替代方案正在雌性小鼠的肝脏中以 17β-雌二醇依赖性方式发生，其机制仍然未知。最近的研究扩展了我们对 PCSK9 生物学功能的理解，即它在感染性休克、血管炎症、病毒感染（登革热；SARS-CoV-2）或癌症免疫检查点调节中的意义通过调节 T 细胞受体和 MHC-I 的细胞表面水平，它们控制 CD8 ⁺ T 细胞的抗肿瘤活性。因为 PCSK9 抑制在这些过程中可能是有利的，所以可注射的安全 PCSK9 抑制剂 (PCSK9i) 的可用性比他汀类药物的作用降低 50-60% LDLc 是非常有价值的。事实上，可注射的 PCSK9 mAb 或 siRNA 可以添加到当前的癌症/转移免疫疗法中。