Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden.
J Intern Med. 2017 Aug;282(2):116-128. doi: 10.1111/joim.12606. Epub 2017 Mar 26.
The complement system is an arm of innate immunity that aids in the removal of pathogens and dying cells. Due to its harmful, pro-inflammatory potential, complement is controlled by several soluble and membrane-bound inhibitors. This family of complement regulators has been recently extended by the discovery of several new members, and it is becoming apparent that these proteins harbour additional functions. In this review, the current state of knowledge of the physiological functions of four complement regulators will be described: cartilage oligomeric matrix protein (COMP), CUB and sushi multiple domains 1 (CSMD1), sushi domain-containing protein 4 (SUSD4) and CD59. Complement activation is involved in both the development of and defence against cancer. COMP expression is pro-oncogenic, whereas CSMD1 and SUSD4 act as tumour suppressors. These effects may be related in part to the complex influence of complement on cancer but also depend on unrelated functions such as the protection of cells from endoplasmic reticulum stress conveyed by intracellular COMP. CD59 is the main inhibitor of the membrane attack complex, and its deficiency leads to complement attack on erythrocytes and severe haemolytic anaemia, which is now amenable to treatment with an inhibitor of C5 cleavage. Unexpectedly, the intracellular pool of CD59 is crucial for insulin secretion from pancreatic β-cells. This finding is one of several relating to the intracellular functions of complement proteins, which until recently were only considered to be present in the extracellular space. Understanding the alternative functions of complement inhibitors may unravel unexpected links between complement and other physiological systems, but is also important for better design of therapeutic complement inhibition.
补体系统是先天免疫系统的一部分，有助于清除病原体和死亡细胞。由于其潜在的有害炎症作用，补体受到几种可溶性和膜结合抑制剂的控制。随着几种新成员的发现，补体调节蛋白家族的范围最近得到了扩展，并且很明显这些蛋白质具有其他功能。在这篇综述中，将描述四种补体调节蛋白的生理功能的最新知识状态：软骨寡聚基质蛋白 (COMP)、CUB 和 sushi 多结构域 1 (CSMD1)、sushi 结构域蛋白 4 (SUSD4) 和 CD59。补体激活参与癌症的发展和防御。COMP 的表达具有致癌作用，而 CSMD1 和 SUSD4 则作为肿瘤抑制因子发挥作用。这些影响可能部分与补体对癌症的复杂影响有关，但也取决于不相关的功能，例如 COMP 对细胞的保护作用，使其免受内质网应激的影响。CD59 是膜攻击复合物的主要抑制剂，其缺乏会导致补体对红细胞的攻击和严重的溶血性贫血，现在可以用 C5 裂解抑制剂进行治疗。出乎意料的是，CD59 的细胞内池对于胰腺β细胞的胰岛素分泌至关重要。这一发现是与补体蛋白的细胞内功能有关的几个发现之一，直到最近，这些功能仅被认为存在于细胞外空间。了解补体抑制剂的替代功能可能会揭示补体与其他生理系统之间意想不到的联系，但对于更好地设计治疗性补体抑制也很重要。
