Abstract
The membrane attack complex (MAC) of the complement system and Perforin-1 are well characterized innate immune effectors. MAC is composed of C9 and other complement proteins that target the envelope of gram-negative bacteria. Perforin-1 is deployed when killer lymphocytes degranulate to destroy virally infected or cancerous cells. These molecules polymerize with MAC-perforin/cholesterol-dependent cytolysin (MACPF/CDC) domains of each monomer deploying amphipathic β-strands to form pores through target lipid bilayers. In this review we discuss one of the most recently discovered members of this family; Perforin-2, the product of the Mpeg1 gene. Since their initial description more than 100 years ago, innumerable studies have made macrophages and other phagocytes some of the best understood cells of the immune system. Yet remarkably it was only recently revealed that Perforin-2 underpins a pivotal function of phagocytes; the destruction of phagocytosed microbes. Several studies have established that phagocytosed bacteria persist and in some cases flourish within phagocytes that lack Perforin-2. When challenged with either gram-negative or gram-positive pathogens Mpeg1 knockout mice succumb to infectious doses that the majority of wild-type mice survive. As expected by their immunocompromised phenotype, bacterial pathogens replicate and disseminate to deeper tissues of Mpeg1 knockout mice. Thus, this evolutionarily ancient gene endows phagocytes with potent bactericidal capability across taxa spanning sponges to humans. The recently elucidated structures of mammalian Perforin-2 reveal it to be a homopolymer that depends upon low pH, such as within phagosomes, to transition to its membrane-spanning pore conformation. Clinical manifestations of Mpeg1 missense mutations further highlight the pivotal role of Perforin-2 within phagocytes. Controversies and gaps within the field of Perforin-2 research are also discussed as well as animal models that may be used to resolve the outstanding issues. Our review concludes with a discussion of bacterial counter measures against Perforin-2.
Highlights
Perforin-2 is a member of the Membrane Attack Complex, Perforin/Cholesterol-Dependent Cytolysin (MACPF/CDC) superfamily of proteins [1]
Timing is likely critical: L. monocytogenes must escape the vacuole before Perforin-2 delivers its lethal blow. Consistent with this hypothesis significantly more bacteria escape to the cytosol of Mpeg1 −/− than wild-type macrophages in cell based assays [52]
In our reinterpretation of the available data we propose that fewer L. monocytogenes reside within acidic vacuoles because acid activates Perforin-2 which facilitates the destruction of vacuolar bacteria
Summary
Perforin-2 is a member of the Membrane Attack Complex, Perforin/Cholesterol-Dependent Cytolysin (MACPF/CDC) superfamily of proteins [1]. In aggregate studies across species of invertebrates and bony fish have shown that infection and/or PAMPs induce the expression of Mpeg1. Structural studies have shown that the P2 domain is likely intrinsic to polymerization and pore formation as it forms the outer ring of both pre-pores and pores with extensive surface area contacts between adjacent P2 domains and MACPFs (Figure 3) [20, 21].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
