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.

Reviewing Editor

  1. Pascale Cossart, Institut Pasteur, France

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.

Version 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.

Metrics

  • 2,101
    Page views
  • 478
    Downloads
  • 33
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.06505

Further reading

    1. Genetics and Genomics
    2. Immunology and Inflammation
    Xinjian Ye, Yijing Bai ... Qianming Chen
    Research Article

    Periodontitis drives irreversible destruction of periodontal tissue and is prone to exacerbating inflammatory disorders. Systemic immunomodulatory management continues to be an attractive approach in periodontal care, particularly within the context of ‘predictive, preventive, and personalized’ periodontics. The present study incorporated genetic proxies identified through genome-wide association studies for circulating immune cells and periodontitis into a comprehensive Mendelian randomization (MR) framework. Univariable MR, multivariable MR, subgroup analysis, reverse MR, and Bayesian model averaging (MR-BMA) were utilized to investigate the causal relationships. Furthermore, transcriptome-wide association study and colocalization analysis were deployed to pinpoint the underlying genes. Consequently, the MR study indicated a causal association between circulating neutrophils, natural killer T cells, plasmacytoid dendritic cells, and an elevated risk of periodontitis. MR-BMA analysis revealed that neutrophils were the primary contributors to periodontitis. The high-confidence genes S100A9 and S100A12, located on 1q21.3, could potentially serve as immunomodulatory targets for neutrophil-mediated periodontitis. These findings hold promise for early diagnosis, risk assessment, targeted prevention, and personalized treatment of periodontitis. Considering the marginal association observed in our study, further research is required to comprehend the biological underpinnings and ascertain the clinical relevance thoroughly.

    1. Developmental Biology
    2. Immunology and Inflammation
    Amir Hossein Kayvanjoo, Iva Splichalova ... Elvira Mass
    Research Article

    During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the murine fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.