Guntermann Silvia, Fraser Brittany, Hazes Bart, Foley Edan
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alta., Canada.
J Innate Immun. 2015;7(5):518-29. doi: 10.1159/000381475. Epub 2015 May 6.
The Drosophila immune deficiency pathway defends many bacterial pathogens and bears striking molecular similarities to the mammalian tumor necrosis factor signal transduction pathway. Orthologous inhibitors of apoptosis ubiquitin ligases act at a proximal stage of both responses to coordinate the assembly of signal transduction platforms that shape host immune responses. Despite the importance of inhibitor of apoptosis proteins within evolutionarily conserved innate immune responses, we know relatively little about the cellular machinery that controls inhibitor of apoptosis activity. In this study, we examined the molecular basis for inhibitor of apoptosis 2 protein regulation in the immune deficiency pathway. Our studies identified two distinct proteolytic events that determine the stability and composition of cellular inhibitor of apoptosis 2 protein pools. We found that apoptotic caspase activity cleaves inhibitor of apoptosis 2 at an N-terminal aspartate to generate a truncated protein that retains the ability to interact with immune deficiency pathway members. We also showed that a C-terminal ubiquitin ligase activity within inhibitor of apoptosis 2 directs the proteasomal destruction of full-length and truncated inhibitor of apoptosis 2 isoforms. These studies add to our appreciation of the regulation of innate immunity and suggest potential links between apoptotic caspases and innate defenses.
果蝇免疫缺陷途径可抵御多种细菌病原体，并且在分子层面与哺乳动物肿瘤坏死因子信号转导途径有着显著的相似性。凋亡抑制蛋白泛素连接酶的直系同源物在这两种反应的近端阶段发挥作用，以协调信号转导平台的组装，从而塑造宿主免疫反应。尽管凋亡抑制蛋白在进化上保守的固有免疫反应中很重要，但我们对控制凋亡抑制活性的细胞机制了解相对较少。在这项研究中，我们研究了免疫缺陷途径中凋亡抑制蛋白2的调控分子基础。我们的研究确定了两种不同的蛋白水解事件，它们决定了细胞中凋亡抑制蛋白2蛋白池的稳定性和组成。我们发现凋亡半胱天冬酶活性在N端天冬氨酸处切割凋亡抑制蛋白2，产生一种截短的蛋白，该蛋白保留了与免疫缺陷途径成员相互作用的能力。我们还表明，凋亡抑制蛋白2内的C端泛素连接酶活性指导全长和截短的凋亡抑制蛋白2亚型的蛋白酶体降解。这些研究增进了我们对固有免疫调节的认识，并提示了凋亡半胱天冬酶与固有防御之间的潜在联系。
