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

Mohamed F. Mohamed, Kajal Gupta, Josef W. Goldufsky, Ruchi Roy, Lauren T. Callaghan, Dawn M. Wetzel, Timothy M. Kuzel, Jochen Reiser and Sasha H. Shafikhani ()
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Mohamed F. Mohamed: Rush University Medical Center
Kajal Gupta: Rush University Medical Center
Josef W. Goldufsky: Rush University Medical Center
Ruchi Roy: Rush University Medical Center
Lauren T. Callaghan: University of Texas Southwestern Medical Center
Dawn M. Wetzel: University of Texas Southwestern Medical Center
Timothy M. Kuzel: Rush University Medical Center
Jochen Reiser: Rush University Medical Center
Sasha H. Shafikhani: Rush University Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28967-5

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