Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Immunobiology. 2012 Nov;217(11):1057-66. doi: 10.1016/j.imbio.2012.07.016.
The complement network is increasingly recognized as an important triage system that is able to differentiate between healthy host cells, microbial intruders, cellular debris and immune complexes, and tailor its actions accordingly. At the center of this triage mechanism is the alternative pathway C3 convertase (C3bBb), a potent enzymatic protein complex capable of rapidly converting the inert yet abundant component C3 into powerful effector fragments (C3a and C3b), thereby amplifying the initial response on unprotected surfaces and inducing a variety of effector functions. A fascinating molecular mechanism of convertase assembly and intrinsic regulation, as well as the interplay with a panel of cell surface-bound and soluble inhibitors are essential for directing complement attack to intruders and protecting healthy host cells. While efficiently keeping immune surveillance and homeostasis on track, the reliance on an intricate cascade of interaction and conversion steps also renders the C3 convertase vulnerable to derail. On the one hand, tissue damage, accumulation of debris, or polymorphisms in complement genes may unfavorably shift the balance between activation and regulation, thereby contributing to a variety of clinical conditions. On the other hand, pathogens developed powerful evasion strategies to avoid complement attack by targeting the convertase. Finally, we increasingly challenge our bodies with foreign materials such as biomaterial implants or drug delivery vehicles that may induce adverse effects that are at least partially caused by complement activation and amplification via the alternative pathway. The involvement of the C3 convertase in a range of pathological conditions put this complex into the spotlight of complement-targeted drug discovery efforts. Fortunately, the physiological regulation and microbial evasion approaches provide a rich source of inspiration for the development of powerful treatment options. This review provides insight into the current knowledge about the molecular mechanisms that drive C3 convertase activity, reveals common and divergent strategies of convertase inhibition employed by host and pathogens, and how this inhibitory arsenal can be tapped for developing therapeutic options to treat complement-related diseases.
补体系统日益被认为是一种重要的分诊系统，能够区分健康宿主细胞、微生物入侵者、细胞碎片和免疫复合物，并相应地调整其作用。在这个分诊机制的中心是替代途径 C3 转化酶（C3bBb），它是一种强大的酶蛋白复合物，能够将惰性但丰富的 C3 成分迅速转化为有效的效应片段（C3a 和 C3b），从而在无保护表面上放大初始反应，并诱导多种效应功能。转化酶组装和固有调节的迷人分子机制，以及与一系列细胞表面结合和可溶性抑制剂的相互作用，对于指导补体攻击入侵者和保护健康宿主细胞至关重要。虽然有效地保持免疫监测和体内平衡，但对复杂的相互作用和转化步骤的依赖也使 C3 转化酶容易受到干扰。一方面，组织损伤、碎片积累或补体基因的多态性可能不利于激活和调节之间的平衡，从而导致多种临床病症。另一方面，病原体发展了强大的逃避策略，通过靶向转化酶来避免补体攻击。最后，我们越来越多地用外来物质（如生物材料植入物或药物输送载体）挑战我们的身体，这些物质可能会引起不良反应，至少部分是由补体通过替代途径激活和放大引起的。C3 转化酶在一系列病理条件中的参与使这种复杂情况成为补体靶向药物发现努力的焦点。幸运的是，生理调节和微生物逃避策略为开发强大的治疗方案提供了丰富的灵感来源。本综述深入了解了驱动 C3 转化酶活性的分子机制的最新知识，揭示了宿主和病原体采用的常见和不同的转化酶抑制策略，以及如何利用这种抑制武器库来开发治疗补体相关疾病的治疗方案。
