ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, VIC, Australia.
Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.
Front Immunol. 2020 Oct 15;11:581906. doi: 10.3389/fimmu.2020.581906. eCollection 2020.
Macrophage-expressed gene 1 [MPEG1/Perforin-2 (PRF2)] is an ancient metazoan protein belonging to the Membrane Attack Complex/Perforin (MACPF) branch of the MACPF/Cholesterol Dependent Cytolysin (CDC) superfamily of pore-forming proteins (PFPs). MACPF/CDC proteins are a large and extremely diverse superfamily that forms large transmembrane aqueous channels in target membranes. In humans, MACPFs have known roles in immunity and development. Like perforin (PRF) and the membrane attack complex (MAC), MPEG1 is also postulated to perform a role in immunity. Indeed, bioinformatic studies suggest that gene duplications of MPEG1 likely gave rise to PRF and MAC components. Studies reveal partial or complete loss of MPEG1 causes an increased susceptibility to microbial infection in both cells and animals. To this end, MPEG1 expression is upregulated in response to proinflammatory signals such as tumor necrosis factor α (TNFα) and lipopolysaccharides (LPS). Furthermore, germline mutations in MPEG1 have been identified in connection with recurrent pulmonary mycobacterial infections in humans. Structural studies on MPEG1 revealed that it can form oligomeric pre-pores and pores. Strikingly, the unusual domain arrangement within the MPEG1 architecture suggests a novel mechanism of pore formation that may have evolved to guard against unwanted lysis of the host cell. Collectively, the available data suggest that MPEG1 likely functions as an intracellular pore-forming immune effector. Herein, we review the current understanding of MPEG1 evolution, regulation, and function. Furthermore, recent structural studies of MPEG1 are discussed, including the proposed mechanisms of action for MPEG1 bactericidal activity. Lastly limitations, outstanding questions, and implications of MPEG1 models are explored in the context of the broader literature and in light of newly available structural data.
巨噬细胞表达基因 1 [MPEG1/穿孔素-2 (PRF2)] 是一种古老的后生动物蛋白，属于膜攻击复合物/穿孔素 (MACPF) 分支的膜孔形成蛋白 (PFP) 家族。MACPF/CDC 蛋白是一个庞大且极其多样化的超家族，它在靶细胞膜中形成大的跨膜水通道。在人类中，MACPF 已知在免疫和发育中发挥作用。与穿孔素 (PRF) 和膜攻击复合物 (MAC) 一样，MPEG1 也被认为在免疫中发挥作用。事实上，生物信息学研究表明，MPEG1 的基因重复可能导致了 PRF 和 MAC 成分的产生。研究表明，MPEG1 的部分或完全缺失会导致细胞和动物对微生物感染的易感性增加。为此，MPEG1 的表达会被肿瘤坏死因子 α (TNFα) 和脂多糖 (LPS) 等促炎信号上调。此外，已经在人类中发现了与反复肺部分枝杆菌感染相关的 MPEG1 种系突变。对 MPEG1 的结构研究表明，它可以形成寡聚前孔和孔。引人注目的是，MPEG1 结构内不寻常的结构域排列表明了一种新的孔形成机制，该机制可能是为了防止宿主细胞的意外裂解而进化而来的。总的来说，现有数据表明 MPEG1 可能作为一种细胞内孔形成免疫效应物发挥作用。本文综述了 MPEG1 进化、调控和功能的最新研究进展。此外，还讨论了最近对 MPEG1 的结构研究，包括对 MPEG1 杀菌活性的作用机制的建议。最后，根据更广泛的文献和新的结构数据，探讨了 MPEG1 模型的局限性、悬而未决的问题和意义。
