Breaching the Bacterial Envelope: The Pivotal Role of Perforin-2 (MPEG1) Within Phagocytes

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.

Effects of Multispecies Probiotic on Intestinal Microbiota and Mucosal Barrier Function of Neonatal Calves Infected With E. coli K99

“…The microbial host-protein interaction map indicated that HSP90 was associated with the host protein, Q3MHN2, which participates in the immune system process and responds to stimuli affecting the host. Q3MHN2 contains a membrane attack complex (MAC)/perforin domain, and the MAC of the complement system is a well-characterized innate immune effector (Merselis et al, 2021). These findings proved that the relationship between neonatal calves infected by E. coli K99 and Batrachochytrium salamandrivorans may be at the strain level instead of at the species level, and that its sub-species level dysbiosis may be related to differences between immune functions in response to oxidative stress.…”

Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway

“…Rho GDIα retains CDC42, RAC1, and RHOA in inactive cytosolic pool and keeps it from degradation ( 43 ). MPEG1 (macrophage expressed gene 1) inhibits the acidification of phagocytic vacuole ( 44 ). Blockade of CD74 receptor or its ligand macrophage migration inhibitory factor (MIF) reduces cell invagination ( 45 ).…”

Small Molecule Inhibitors of Lymphocyte Perforin as Focused Immunosuppressants for Infection and Autoimmunity

“… 63 The terminal membrane attack complex (MAC) complement components C5b, C6, and C7–9 of mammals also all share a MACPf fold with perforin. However, none of the complement components or the distantly related bacteriocidal macrophage protein perforin-2 64 have a C2 domain. Other more distant human pore-forming proteins such as gasdermin D 65 and antimicrobial toxin granulysin 66 have no structural similarity to perforin and are not blocked by perforin inhibitors.…”