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

Abstract

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.

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, may gain royalties from commercialization of USPTO patent applications PCT/US2014/059675 and PCT/US2013/032503.
  2. Kirill Lyapichev

    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    Kirill Lyapichev, may gain royalties from commercialization of USPTO patent applications PCT/US2014/059675 and PCT/US2013/032503.
  3. Melissa L Olsson

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

    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    Eckhard R Podack, may gain royalties from commercialization of USPTO patent applications PCT/US2014/059675 and PCT/US2013/032503.
  5. George P Munson

    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States
    For correspondence
    gmunson@miami.edu
    Competing interests
    No competing interests declared.

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 Research Council as stipulated by 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 #12-257) of the University of Miami Miller School of Medicine.

Reviewing Editor

  1. Pascale Cossart, Institut Pasteur, France

Publication history

  1. Received: January 15, 2015
  2. Accepted: September 28, 2015
  3. Accepted Manuscript published: September 29, 2015 (version 1)
  4. Version of Record published: October 30, 2015 (version 2)

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. Kirill Lyapichev
  3. Melissa L Olsson
  4. Eckhard R Podack
  5. George P Munson
(2015)
Enteric pathogens deploy cell cycle inhibiting factors to block the bactericidal activity of Perforin-2
eLife 4:e06505.
https://doi.org/10.7554/eLife.06505

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