1. Immunology and Inflammation
  2. Microbiology and Infectious Disease

Perforin-2 is essential for intracellular defense of parenchymal cells and phagocytes against pathogenic bacteria

  1. Ryan M McCormack
  2. Lesley R de Armas
  3. Motoaki Shiratsuchi
  4. Desiree G Fiorentino
  5. Melissa L Olsson
  6. Mathias G Lichtenheld
  7. Alejo Morales
  8. Kirill Lyapichev
  9. Louis E Gonzalez
  10. Natasa Strbo
  11. Neelima Sukumar
  12. Olivera Stojadinovic
  13. Gregory V Plano
  14. George P Munson
  15. Marjana Tomic-Canic
  16. Robert S Kirsner
  17. David G Russell
  18. Eckhard R Podack  Is a corresponding author
  1. University of Miami, United States
  2. Cornell University, United States
  3. U. Miami, School of Medicine, United States
https://doi.org/10.7554/eLife.06508
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Cite this article
  1. Ryan M McCormack
  2. Lesley R de Armas
  3. Motoaki Shiratsuchi
  4. Desiree G Fiorentino
  5. Melissa L Olsson
  6. Mathias G Lichtenheld
  7. Alejo Morales
  8. Kirill Lyapichev
  9. Louis E Gonzalez
  10. Natasa Strbo
  11. Neelima Sukumar
  12. Olivera Stojadinovic
  13. Gregory V Plano
  14. George P Munson
  15. Marjana Tomic-Canic
  16. Robert S Kirsner
  17. David G Russell
  18. Eckhard R Podack
(2015)
Perforin-2 is essential for intracellular defense of parenchymal cells and phagocytes against pathogenic bacteria
eLife 4:e06508.
https://doi.org/10.7554/eLife.06508
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  3. Download .RIS

Abstract

Perforin-2 (MPEG1) is a pore-forming, antibacterial protein with broad-spectrum activity. Perforin-2 is expressed constitutively in phagocytes and inducibly in parenchymal, tissue-forming cells. In vitro, Perforin-2 prevents the intracellular replication and proliferation of bacterial pathogens in these cells. Perforin-2 knockout mice are unable to control the systemic dissemination of methicillin-resistant Staphylococcus aureus (MRSA) or Salmonella typhimurium and perish shortly after epicutaneous or orogastric infection respectively. In contrast, Perforin-2-sufficient littermates clear the infection. Perforin-2 is a transmembrane protein of cytosolic vesicles -derived from multiple organelles- that translocate to and fuse with bacterium containing vesicles. Subsequently, Perforin-2 polymerizes and forms large clusters of 100Å pores in the bacterial surface with Perforin-2 cleavage products present in bacteria. Perforin-2 is also required for the bactericidal activity of reactive oxygen and nitrogen species and hydrolytic enzymes. Perforin-2 constitutes a novel and apparently essential bactericidal effector molecule of the innate immune system.

Article and author information

Author details

  1. Ryan M McCormack

    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    Ryan M McCormack, This author is an inventor of patents used in the study and stand to gain royalties from future commercialization..

  2. Lesley R de Armas

    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    Lesley R de Armas, This author is an inventor of patents used in the study and stand to gain royalties from future commercialization..

  3. Motoaki Shiratsuchi

    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  4. Desiree G Fiorentino

    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  5. Melissa L Olsson

    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  6. Mathias G Lichtenheld

    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  7. Alejo Morales

    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  8. Kirill Lyapichev

    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    Kirill Lyapichev, This author is an inventor of patents used in the study and stand to gain royalties from future commercialization..

  9. Louis E Gonzalez

    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  10. Natasa Strbo

    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  11. Neelima Sukumar

    Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, United States
    Competing interests
    No competing interests declared.

  12. Olivera Stojadinovic

    Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  13. Gregory V Plano

    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  14. George P Munson

    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  15. Marjana Tomic-Canic

    Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  16. Robert S Kirsner

    Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  17. David G Russell

    Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, United States
    Competing interests
    No competing interests declared.

  18. Eckhard R Podack

    Microbiology and Immunology, U. Miami, School of Medicine, Miami, United States
    For correspondence
    epodack@miami.edu
    Competing interests
    Eckhard R Podack, This author is an inventor of patents used in the study and stand to gain royalties from future commercialization..

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#13-233 and #12-259) of the University of Miami Miller School of Medicine.

Copyright

© 2015, McCormack et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ryan M McCormack
  2. Lesley R de Armas
  3. Motoaki Shiratsuchi
  4. Desiree G Fiorentino
  5. Melissa L Olsson
  6. Mathias G Lichtenheld
  7. Alejo Morales
  8. Kirill Lyapichev
  9. Louis E Gonzalez
  10. Natasa Strbo
  11. Neelima Sukumar
  12. Olivera Stojadinovic
  13. Gregory V Plano
  14. George P Munson
  15. Marjana Tomic-Canic
  16. Robert S Kirsner
  17. David G Russell
  18. Eckhard R Podack
(2015)
Perforin-2 is essential for intracellular defense of parenchymal cells and phagocytes against pathogenic bacteria
eLife 4:e06508.
https://doi.org/10.7554/eLife.06508

Share this article

https://doi.org/10.7554/eLife.06508

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Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease

    Enteric pathogens deploy cell cycle inhibiting factors to block the bactericidal activity of Perforin-2

    Ryan M McCormack, Kirill Lyapichev ... George P Munson
    Research Article Updated

    Perforin-2 (MPEG1) is an effector of the innate immune system that limits the proliferation and spread of medically relevant Gram-negative, -positive, and acid fast bacteria. We show here that a cullin-RING E3 ubiquitin ligase (CRL) complex containing cullin-1 and βTrCP monoubiquitylates Perforin-2 in response to pathogen associated molecular patterns such as LPS. Ubiquitylation triggers a rapid redistribution of Perforin-2 and is essential for its bactericidal activity. Enteric pathogens such as Yersinia pseudotuberculosis and enteropathogenic Escherichia coli disarm host cells by injecting cell cycle inhibiting factors (Cifs) into mammalian cells to deamidate the ubiquitin-like protein NEDD8. Because CRL activity is dependent upon NEDD8, Cif blocks ubiquitin dependent trafficking of Perforin-2 and thus, its bactericidal activity. Collectively, these studies further underscore the biological significance of Perforin-2 and elucidate critical molecular events that culminate in Perforin-2-dependent killing of both intracellular and extracellular, cell-adherent bacteria.