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

Merselis, Leidy C., Rivas, Zachary P., Munson, George P.·2021·Frontiers in Immunology
DOI 10.3389/fimmu.2021.597951PMC PMC7937864
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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.

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Figures

Figure 1 Domain Organization of Mammalian C9 and Perforins. Each of the immune effectors contains a signal peptide (SP), membrane attack complex perforin (MACPF), and epidermal growth factor-like (EGF) domains. However, the latter is truncated in Perforin-2. The P2 domain is unique to Perforin-2 and has been evolutionarily conserved across taxa. Recent structural and functional studies suggest the P2 domain initiates contact with target membranes. However, this does not preclude other putative functions such oligomerization and/or ring stabilization. Another distinctive feature of Perforin-2 is a transmembrane domain (TM) near its carboxy terminus. Although Perforin-2 is initially a Type I transmembrane protein, it is likely cleaved from its TM domain as it is delivered to phagosomes to facilitate oligomerization and pore formation. The TM domain is followed by a short cytosolic tail that is involved in the intracellular trafficking of Perforin-2 to phagosomes. TSP1, thrombospondin type-1 repeat; LDL, low-density lipoprotein receptor class A repeat; C2, calcium-dependent phospholipid binding domain; CTR, carboxy-terminal region.
Figure 1 Domain Organization of Mammalian C9 and Perforins. Each of the immune effectors contains a signal peptide (SP), membrane attack complex perforin (MACPF), and epidermal growth factor-like (EGF) domains. However, the latter is truncated in Perforin-2. The P2 domain is unique to Perforin-2 and has been evolutionarily conserved across taxa. Recent structural and functional studies suggest the P2 domain initiates contact with target membranes. However, this does not preclude other putative functions such oligomerization and/or ring stabilization. Another distinctive feature of Perforin-2 is a transmembrane domain (TM) near its carboxy terminus. Although Perforin-2 is initially a Type I transmembrane protein, it is likely cleaved from its TM domain as it is delivered to phagosomes to facilitate oligomerization and pore formation. The TM domain is followed by a short cytosolic tail that is involved in the intracellular trafficking of Perforin-2 to phagosomes. TSP1, thrombospondin type-1 repeat; LDL, low-density lipoprotein receptor class A repeat; C2, calcium-dependent phospholipid binding domain; CTR, carboxy-terminal region.CC BY · PubMed Central
Figure 2 The P2 domain of murine Perforin-2. The most prominent feature within the P2 domain is an extended β-hairpin; highlighted in dark orange. Two disulfide bonds stiffen the β-hairpin. Hydrophobic residues at the β-hairpin’s tip are shown in dark green. These residues likely orient Perforin-2 on phagocytosed bacteria by initiating contact with target lipid bilayers. Numbering is relative to UniProt accession number A1L314. This graphic was rendered with UCSF Chimera from PDB file 6SB1 (http://www.rcsb.org/structure/6SB1) (20).
Figure 2 The P2 domain of murine Perforin-2. The most prominent feature within the P2 domain is an extended β-hairpin; highlighted in dark orange. Two disulfide bonds stiffen the β-hairpin. Hydrophobic residues at the β-hairpin’s tip are shown in dark green. These residues likely orient Perforin-2 on phagocytosed bacteria by initiating contact with target lipid bilayers. Numbering is relative to UniProt accession number A1L314. This graphic was rendered with UCSF Chimera from PDB file 6SB1 (http://www.rcsb.org/structure/6SB1) (20).CC BY · PubMed Central
Figure 3 The pre-pore and acid-dependent pore of murine Perforin-2 from top and side views. Each polymer is composed of 16 subunits. MACPF domains line the interior of each polymer and are depicted in alternating shades of green. P2 domains are depicted as orange ribbons that encircle the exterior of each polymer. A truncated EGF domain, light gray, links the MACPF and P2 domains. The carboxy-terminal region is shown in black. This region is visible in the pre-pore but was not resolved in the pore. Images were rendered with UCSF Chimera from PDB files 6SB3 (http://www.rcsb.org/structure/6SB3) and 6SB5 (http://www.rcsb.org/structure/6SB5) (20).
Figure 3 The pre-pore and acid-dependent pore of murine Perforin-2 from top and side views. Each polymer is composed of 16 subunits. MACPF domains line the interior of each polymer and are depicted in alternating shades of green. P2 domains are depicted as orange ribbons that encircle the exterior of each polymer. A truncated EGF domain, light gray, links the MACPF and P2 domains. The carboxy-terminal region is shown in black. This region is visible in the pre-pore but was not resolved in the pore. Images were rendered with UCSF Chimera from PDB files 6SB3 (http://www.rcsb.org/structure/6SB3) and 6SB5 (http://www.rcsb.org/structure/6SB5) (20).CC BY · PubMed Central
Figure 4 Perforin-2 facilitates protease entry to the periplasmic space. Shortly after microbe phagocytosis Perforin-2 is delivered to the phagosome and deposits on the bacterial envelope. As the phagosome acidifies pre-pores transition to pores that breach the outer membrane. This allows proteases to enter the periplasmic space and begin the digestion of periplasmic and inner membrane proteins. In the absence of Perforin-2 phagosomal proteases are restricted to digestion of outer membrane proteins such as flagellin. This graphic is an adaptation from a previously published version (26).
Figure 4 Perforin-2 facilitates protease entry to the periplasmic space. Shortly after microbe phagocytosis Perforin-2 is delivered to the phagosome and deposits on the bacterial envelope. As the phagosome acidifies pre-pores transition to pores that breach the outer membrane. This allows proteases to enter the periplasmic space and begin the digestion of periplasmic and inner membrane proteins. In the absence of Perforin-2 phagosomal proteases are restricted to digestion of outer membrane proteins such as flagellin. This graphic is an adaptation from a previously published version (26).CC BY · PubMed Central
Figure 5 Mpeg1::mCherry reporters facilitate the tracking of macrophages in larval zebrafish. Because the expression of Perforin-2 is largely restricted to macrophages in zebrafish, the insertion of mCherry into the Mpeg1 locus allows localization of macrophages in both fixed and live animals. The transgenic animals above were infected with sublethal and lethal doses of Shigella flexneri and fixed 24 h post infection. The above images have been previously published (58) and are a composite of the red and green fluorescent channels. This figure was adapted from source images posted at https://doi.org/10.1371/journal.ppat.1003588.g002 under the CC BY 4.0 license.
Figure 5 Mpeg1::mCherry reporters facilitate the tracking of macrophages in larval zebrafish. Because the expression of Perforin-2 is largely restricted to macrophages in zebrafish, the insertion of mCherry into the Mpeg1 locus allows localization of macrophages in both fixed and live animals. The transgenic animals above were infected with sublethal and lethal doses of Shigella flexneri and fixed 24 h post infection. The above images have been previously published (58) and are a composite of the red and green fluorescent channels. This figure was adapted from source images posted at https://doi.org/10.1371/journal.ppat.1003588.g002 under the CC BY 4.0 license.CC BY · PubMed Central
Figure 6 Peforin-2 deficient mice are immunocompromised. (A) Survival curves of wild-type, Mpeg1 +/−, and −/− C57Bl/6 x 129X1/SvJ mice after orogastric inoculation with 106 CFU Y. pseudotuberculosis or 105 CFU S. Typhimurium. P values determined by Log-rank (Mantel-Cox) test. (B) Organ loads of wild-type, Mpeg1 +/−, and −/− C57Bl/6 x 129X1/SvJ mice after orogastric inoculation with 106 CFU Y. pseudotuberculosis or 105 CFU S. Typhimurium. The former group of animals were sacrificed 10 days post inoculation while the latter were sacrificed 5 days post inoculation. Horizontal bars denote the medians. P values were determined by non-parametric Kruskal-Wallis test. This figure was adapted from previously published work (15, 19) from source data posted at https://doi.org/10.35092/yhjc.12584993.v1 under the CC BY 4.0 license. Sm. Int., small intestine.
Figure 6 Peforin-2 deficient mice are immunocompromised. (A) Survival curves of wild-type, Mpeg1 +/−, and −/− C57Bl/6 x 129X1/SvJ mice after orogastric inoculation with 106 CFU Y. pseudotuberculosis or 105 CFU S. Typhimurium. P values determined by Log-rank (Mantel-Cox) test. (B) Organ loads of wild-type, Mpeg1 +/−, and −/− C57Bl/6 x 129X1/SvJ mice after orogastric inoculation with 106 CFU Y. pseudotuberculosis or 105 CFU S. Typhimurium. The former group of animals were sacrificed 10 days post inoculation while the latter were sacrificed 5 days post inoculation. Horizontal bars denote the medians. P values were determined by non-parametric Kruskal-Wallis test. This figure was adapted from previously published work (15, 19) from source data posted at https://doi.org/10.35092/yhjc.12584993.v1 under the CC BY 4.0 license. Sm. Int., small intestine.CC BY · PubMed Central
Figure 7 Glycosylated Asn185 and Asn269 are located on opposite faces of the MACPF domain. A monomer of murine Perforin-2 shown in (Left) full view and (Middle & Right) progressive cross-sections into the molecule. The MACPF and P2 domains are shaded green and orange respectively. The truncated EGF domain, which connects the MACPF and P2 domains, is shaded grey and is partially visible in the upper right of the far right image. The extended carboxy terminal region is shown in tan. Asn185 and 269 are conserved and glycosylated in both murine and human Perforin-2 (20, 21). Their glycans are shown as pink spheres. In contrast to the MACPFs, the P2 domains of both species are devoid of glycosylation. This includes the absence of glycosylation of Asn375; shaded deep blue above and visible in the middle image. Images were rendered with UCSF Chimera from PDB file 6SB3 (http://www.rcsb.org/structure/6SB3) (20). Residue numbering is relative to UniProt entry A1L314 (https://www.uniprot.org/uniprot/A1L314).
Figure 7 Glycosylated Asn185 and Asn269 are located on opposite faces of the MACPF domain. A monomer of murine Perforin-2 shown in (Left) full view and (Middle & Right) progressive cross-sections into the molecule. The MACPF and P2 domains are shaded green and orange respectively. The truncated EGF domain, which connects the MACPF and P2 domains, is shaded grey and is partially visible in the upper right of the far right image. The extended carboxy terminal region is shown in tan. Asn185 and 269 are conserved and glycosylated in both murine and human Perforin-2 (20, 21). Their glycans are shown as pink spheres. In contrast to the MACPFs, the P2 domains of both species are devoid of glycosylation. This includes the absence of glycosylation of Asn375; shaded deep blue above and visible in the middle image. Images were rendered with UCSF Chimera from PDB file 6SB3 (http://www.rcsb.org/structure/6SB3) (20). Residue numbering is relative to UniProt entry A1L314 (https://www.uniprot.org/uniprot/A1L314).CC BY · PubMed Central
Figure 8 Perforin-2 haploinsufficiency results in the reduced ability of human phagocytes to kill intracellular bacteria. (A) A monomer of human Perforin-2 in its pre-pore conformation. The MACPF and P2 domains are depicted in light green and orange respectively. The carboxy-terminal region is shown in tan. Glycans attached to N185 and N269 are shown as space filling models. Also shown are the positions of deleterious missense (magenta) and nonsense (cyan) mutations (90, 91). Residue numbering is relative to relative to UniProt entry Q2M385 (https://www.uniprot.org/uniprot/Q2M385). (B) Killing of intracellular S. Typhimurium by neutrophils isolated from the blood of a donor carrying a heterozygous Y430* nonsense mutation or healthy controls. Relative bacterial colony forming units are reported as Log2 Fold Change = log2(CFU at time X) – log2(CFU at time initial). **P < 0.01 by 2way ANOVA. This figure was adapted from previously published work (91) under the CC BY 4.0 license. Molecular graphics were rendered with UCSF ChimeraX from PDB file 6U2J (http://www.rcsb.org/structure/6U2J) (21).
Figure 8 Perforin-2 haploinsufficiency results in the reduced ability of human phagocytes to kill intracellular bacteria. (A) A monomer of human Perforin-2 in its pre-pore conformation. The MACPF and P2 domains are depicted in light green and orange respectively. The carboxy-terminal region is shown in tan. Glycans attached to N185 and N269 are shown as space filling models. Also shown are the positions of deleterious missense (magenta) and nonsense (cyan) mutations (90, 91). Residue numbering is relative to relative to UniProt entry Q2M385 (https://www.uniprot.org/uniprot/Q2M385). (B) Killing of intracellular S. Typhimurium by neutrophils isolated from the blood of a donor carrying a heterozygous Y430* nonsense mutation or healthy controls. Relative bacterial colony forming units are reported as Log2 Fold Change = log2(CFU at time X) – log2(CFU at time initial). **P < 0.01 by 2way ANOVA. This figure was adapted from previously published work (91) under the CC BY 4.0 license. Molecular graphics were rendered with UCSF ChimeraX from PDB file 6U2J (http://www.rcsb.org/structure/6U2J) (21).CC BY · PubMed Central
Figure 9 Y. pseudotuberculosis and EPEC deploy Cifs to block the delivery of Perforin-2 to phagosomes. (A) The cytosolic tail of Perforin-2 is ubiquitinated in response to PAMPs such as LPS. (B) Ubiquitinated Perforin-2 is rapidly delivered to phagosomes where it oligomerizes and (C) phagosome acidification induces the pre-pore to pore transition. (D) The ligase responsible for conjugating ubiquitin to Perforin-2 is a multi-component cullin-RING E3 ubiquitin ligase (CRL) whose activity is itself dependent upon cullin neddylation. (E) Pathogenic Y. pseudotuberculosis and EPEC use Type III secretion systems to inject Cifs into the cytosol of host cells where they deamidate Gln40 of NEDD8. The enzymatic conversion of Gln to Glu inactivates the CRL and thus prevents ubiquitin dependent intracellular trafficking of Perforin-2. N8, NEDD8; Ub, ubiquitin; CUL1, cullin 1.
Figure 9 Y. pseudotuberculosis and EPEC deploy Cifs to block the delivery of Perforin-2 to phagosomes. (A) The cytosolic tail of Perforin-2 is ubiquitinated in response to PAMPs such as LPS. (B) Ubiquitinated Perforin-2 is rapidly delivered to phagosomes where it oligomerizes and (C) phagosome acidification induces the pre-pore to pore transition. (D) The ligase responsible for conjugating ubiquitin to Perforin-2 is a multi-component cullin-RING E3 ubiquitin ligase (CRL) whose activity is itself dependent upon cullin neddylation. (E) Pathogenic Y. pseudotuberculosis and EPEC use Type III secretion systems to inject Cifs into the cytosol of host cells where they deamidate Gln40 of NEDD8. The enzymatic conversion of Gln to Glu inactivates the CRL and thus prevents ubiquitin dependent intracellular trafficking of Perforin-2. N8, NEDD8; Ub, ubiquitin; CUL1, cullin 1.CC BY · PubMed Central
Figure 10 Bacteria lacking the anti-Perforin-2 effector Cif are attenuated in vivo. Survival curves of C57BL/6 mice were orogastrically inoculated with 108 CFU wild-type Y. pseudotuberculosis or an isogenic cif mutant. Significance was calculated by log-rank (Mantel–Cox) test. This figure was adapted from work previously published under the CC BY 4.0 license (19).
Figure 10 Bacteria lacking the anti-Perforin-2 effector Cif are attenuated in vivo. Survival curves of C57BL/6 mice were orogastrically inoculated with 108 CFU wild-type Y. pseudotuberculosis or an isogenic cif mutant. Significance was calculated by log-rank (Mantel–Cox) test. This figure was adapted from work previously published under the CC BY 4.0 license (19).CC BY · PubMed Central

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Cited by

Metadata

Authors
Merselis, L. C., Rivas, Z. P., & Munson, G. P.
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2021-02-22
Volume
12
ISSN
1664-3224
DOI
10.3389/fimmu.2021.597951
PMC
PMC7937864
Cited by
18
References
3
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
National Institutes of Health (R01AI110810, R21AI156567)

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