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CrkII/Abl phosphorylation cascade is critical for NLRC4 inflammasome activity and is blocked by Pseudomonas aeruginosa ExoT

Author

Listed:
  • Mohamed F. Mohamed

    (Rush University Medical Center
    Rush University Medical Center)

  • Kajal Gupta

    (Rush University Medical Center
    Rush University Medical Center)

  • Josef W. Goldufsky

    (Rush University Medical Center
    Rush University Medical Center)

  • Ruchi Roy

    (Rush University Medical Center
    Rush University Medical Center)

  • Lauren T. Callaghan

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Dawn M. Wetzel

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Timothy M. Kuzel

    (Rush University Medical Center
    Rush University Medical Center
    Rush University Medical Center)

  • Jochen Reiser

    (Rush University Medical Center)

  • Sasha H. Shafikhani

    (Rush University Medical Center
    Rush University Medical Center
    Rush University Medical Center
    Rush University Medical Center)

Abstract

Type 3 Secretion System (T3SS) is a highly conserved virulence structure that plays an essential role in the pathogenesis of many Gram-negative pathogenic bacteria, including Pseudomonas aeruginosa. Exotoxin T (ExoT) is the only T3SS effector protein that is expressed in all T3SS-expressing P. aeruginosa strains. Here we show that T3SS recognition leads to a rapid phosphorylation cascade involving Abl / PKCδ / NLRC4, which results in NLRC4 inflammasome activation, culminating in inflammatory responses that limit P. aeruginosa infection in wounds. We further show that ExoT functions as the main anti-inflammatory agent for P. aeruginosa in that it blocks the phosphorylation cascade through Abl / PKCδ / NLRC4 by targeting CrkII, which we further demonstrate to be important for Abl transactivation and NLRC4 inflammasome activation in response to T3SS and P. aeruginosa infection.

Suggested Citation

  • Mohamed F. Mohamed & Kajal Gupta & Josef W. Goldufsky & Ruchi Roy & Lauren T. Callaghan & Dawn M. Wetzel & Timothy M. Kuzel & Jochen Reiser & Sasha H. Shafikhani, 2022. "CrkII/Abl phosphorylation cascade is critical for NLRC4 inflammasome activity and is blocked by Pseudomonas aeruginosa ExoT," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28967-5
    DOI: 10.1038/s41467-022-28967-5
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    References listed on IDEAS

    as
    1. Alessandro Rimessi & Valentino Bezzerri & Simone Patergnani & Saverio Marchi & Giulio Cabrini & Paolo Pinton, 2015. "Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis," Nature Communications, Nature, vol. 6(1), pages 1-16, May.
    2. Yan Qu & Shahram Misaghi & Anita Izrael-Tomasevic & Kim Newton & Laurie L. Gilmour & Mohamed Lamkanfi & Salina Louie & Nobuhiko Kayagaki & Jinfeng Liu & László Kömüves & James E. Cupp & David Arnott &, 2012. "Phosphorylation of NLRC4 is critical for inflammasome activation," Nature, Nature, vol. 490(7421), pages 539-542, October.
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    Cited by:

    1. Martin S. Minns & Karl Liboro & Tatiane S. Lima & Serena Abbondante & Brandon A. Miller & Michaela E. Marshall & Jolynn Tran Chau & Alicia Roistacher & Arne Rietsch & George R. Dubyak & Eric Pearlman, 2023. "NLRP3 selectively drives IL-1β secretion by Pseudomonas aeruginosa infected neutrophils and regulates corneal disease severity," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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