Ho Bill H T, Spicer Bradley A, Dunstone Michelle A
Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia.
J Membr Biol. 2025 Mar 23. doi: 10.1007/s00232-025-00343-6.
The complement pathway is one of the most ancient elements of the host's innate response and includes a set of protein effectors that rapidly react against pathogens. The late stages of the complement reaction are broadly categorised into two major outcomes. Firstly, C5a receptors, expressed on membranes of host cells, are activated by C5a to generate pro-inflammatory responses. Secondly, target cells are lysed by a hetero-oligomeric pore known as the membrane attack complex (MAC) that punctures the cellular membrane, causing ion and osmotic flux. Generally, several membrane-bound and soluble inhibitors protect the host membrane from complement damage. This includes inhibitors against the MAC, such as clusterin and CD59. This review addresses the most recent molecular and structural insights behind the activation and modulation of the integral membrane proteins, the C5a receptors (C5aR1 and C5aR2), as well as the regulation of MAC assembly. The second aspect of the review focuses on the molecular basis behind inflammatory diseases that are reflective of failure to regulate the terminal complement effectors. Although each arm is unique in its function, both pathways may share similar outcomes in these diseases. As such, the review outlines potential synergy and crosstalk between C5a receptor activation and MAC-mediated cellular responses.
补体途径是宿主固有免疫反应中最古老的组成部分之一，包括一组能迅速对病原体作出反应的蛋白质效应分子。补体反应的后期大致可分为两种主要结果。其一，宿主细胞膜上表达的C5a受体被C5a激活，从而产生促炎反应。其二，靶细胞被一种称为膜攻击复合物（MAC）的异源寡聚孔道溶解，该孔道会刺穿细胞膜，导致离子和渗透压变化。一般来说，几种膜结合型和可溶性抑制剂可保护宿主细胞膜免受补体损伤。这包括针对MAC的抑制剂，如簇集素和CD59。本综述阐述了整合膜蛋白C5a受体（C5aR1和C5aR2）激活与调节以及MAC组装调控背后的最新分子和结构见解。综述的第二个方面聚焦于炎症性疾病背后的分子基础，这些疾病反映了终末补体效应分子调节功能的缺失。尽管每条途径在功能上都具有独特性，但在这些疾病中两条途径可能会有相似的结果。因此，本综述概述了C5a受体激活与MAC介导的细胞反应之间潜在的协同作用和相互影响。
