| Structural highlights
Function
[MPEG1_MOUSE] Plays a key role in the innate immune response following bacterial infection by polymerizing and inserting into the bacterial surface to form pores (PubMed:26402460). By breaching the surface of phagocytosed bacteria, allows antimicrobial effectors to enter the bacterial periplasmic space and degrade bacterial proteins such as superoxide dismutase sodC which contributes to bacterial virulence (PubMed:30249808). Shows antibacterial activity against a wide spectrum of Gram-positive, Gram-negative and acid-fast bacteria (PubMed:23257510, PubMed:23753625, PubMed:26402460). Reduces the viability of the intracytosolic pathogen L.monocytogenes by inhibiting acidification of the phagocytic vacuole of host cells which restricts bacterial translocation from the vacuole to the cytosol (PubMed:26831467). Required for the antibacterial activity of reactive oxygen species and nitric oxide (PubMed:26402460).[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Perforin-2 (MPEG1) is thought to enable the killing of invading microbes engulfed by macrophages and other phagocytes, forming pores in their membranes. Loss of perforin-2 renders individual phagocytes and whole organisms significantly more susceptible to bacterial pathogens. Here, we reveal the mechanism of perforin-2 activation and activity using atomic structures of pre-pore and pore assemblies, high-speed atomic force microscopy, and functional assays. Perforin-2 forms a pre-pore assembly in which its pore-forming domain points in the opposite direction to its membrane-targeting domain. Acidification then triggers pore formation, via a 180 degrees conformational change. This novel and unexpected mechanism prevents premature bactericidal attack and may have played a key role in the evolution of all perforin family proteins.
Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity.,Ni T, Jiao F, Yu X, Aden S, Ginger L, Williams SI, Bai F, Prazak V, Karia D, Stansfeld P, Zhang P, Munson G, Anderluh G, Scheuring S, Gilbert RJC Sci Adv. 2020 Jan 29;6(5):eaax8286. doi: 10.1126/sciadv.aax8286. eCollection 2020, Jan. PMID:32064340[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ McCormack R, de Armas LR, Shiratsuchi M, Ramos JE, Podack ER. Inhibition of intracellular bacterial replication in fibroblasts is dependent on the perforin-like protein (perforin-2) encoded by macrophage-expressed gene 1. J Innate Immun. 2013;5(2):185-94. doi: 10.1159/000345249. Epub 2012 Dec 15. PMID:23257510 doi:http://dx.doi.org/10.1159/000345249
- ↑ Fields KA, McCormack R, de Armas LR, Podack ER. Perforin-2 restricts growth of Chlamydia trachomatis in macrophages. Infect Immun. 2013 Aug;81(8):3045-54. doi: 10.1128/IAI.00497-13. Epub 2013 Jun, 10. PMID:23753625 doi:http://dx.doi.org/10.1128/IAI.00497-13
- ↑ McCormack RM, de Armas LR, Shiratsuchi M, Fiorentino DG, Olsson ML, Lichtenheld MG, Morales A, Lyapichev K, Gonzalez LE, Strbo N, Sukumar N, Stojadinovic O, Plano GV, Munson GP, Tomic-Canic M, Kirsner RS, Russell DG, Podack ER. Perforin-2 is essential for intracellular defense of parenchymal cells and phagocytes against pathogenic bacteria. Elife. 2015 Sep 24;4. doi: 10.7554/eLife.06508. PMID:26402460 doi:http://dx.doi.org/10.7554/eLife.06508
- ↑ McCormack R, Bahnan W, Shrestha N, Boucher J, Barreto M, Barrera CM, Dauer EA, Freitag NE, Khan WN, Podack ER, Schesser K. Perforin-2 Protects Host Cells and Mice by Restricting the Vacuole to Cytosol Transitioning of a Bacterial Pathogen. Infect Immun. 2016 Mar 24;84(4):1083-1091. doi: 10.1128/IAI.01434-15. Print 2016 , Apr. PMID:26831467 doi:http://dx.doi.org/10.1128/IAI.01434-15
- ↑ Bai F, McCormack RM, Hower S, Plano GV, Lichtenheld MG, Munson GP. Perforin-2 Breaches the Envelope of Phagocytosed Bacteria Allowing Antimicrobial Effectors Access to Intracellular Targets. J Immunol. 2018 Nov 1;201(9):2710-2720. doi: 10.4049/jimmunol.1800365. Epub 2018 , Sep 24. PMID:30249808 doi:http://dx.doi.org/10.4049/jimmunol.1800365
- ↑ Ni T, Jiao F, Yu X, Aden S, Ginger L, Williams SI, Bai F, Prazak V, Karia D, Stansfeld P, Zhang P, Munson G, Anderluh G, Scheuring S, Gilbert RJC. Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity. Sci Adv. 2020 Jan 29;6(5):eaax8286. doi: 10.1126/sciadv.aax8286. eCollection 2020, Jan. PMID:32064340 doi:http://dx.doi.org/10.1126/sciadv.aax8286
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