Abstract
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.
Highlights
The superfamily of Membrane Attack Complex/Perforin (MACPF)/Cholesterol Dependent Cytolysin (CDC) consists of proteins ubiquitously found in many kingdoms of life, including bacteria, plants, fungi and animals
These early studies led to the identification of the Membrane Attack Complex (MAC), which is the terminal effector of the complement pathway [16]
These experiments suggest that, rather than a protective role, the MVB12-associated b-prism (MABP) b-hairpin may perform a targeting role as an ancillary domain in a more typical MACPF/CDC sense (Figures 6Bvii– viii). In this context the assembly of the prepore occurs independently from the target membrane—this ability itself is unique when compared to other family members. These features suggest that Macrophage-expressed gene 1 (MPEG1), unlike other MACPF/ CDC systems studied to date, may follow a distinct assembly pathway with independent assembly and target membranes
Summary
The superfamily of MACPF/CDCs consists of proteins ubiquitously found in many kingdoms of life, including bacteria, plants, fungi and animals. The suppression of an MPEG1 paralog in zebrafish was observed to reduce the likelihood that fish would succumb to infection [88] Taken together, these studies suggest MPEG1 plays a role in the excessive IFN signaling during an overwhelming immune response. Limited proteolysis experiments of MPEG1-enriched bilayers derived from transfected cells resulted in membrane-bound ring-like oligomers [79], whereas, these oligomers were not observed in the absence of proteolytic treatment This supports the current model whereby the ectodomain is shed during MPEG1 anti-microbial function. These topics have been extensively reviewed elsewhere in detail [15, 17, 18, 58, 98,99,100,101,102]
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