Effector-mediated subversion of proteasome activator (PA)28αβ enhances host defense against Legionella pneumophila under inflammatory and oxidative stress conditions.

Autor: Ngwaga T; Division of Biology, Kansas State University, Manhattan, Kansas, United States of America., Chauhan D; Division of Biology, Kansas State University, Manhattan, Kansas, United States of America., Salberg AG; Division of Biology, Kansas State University, Manhattan, Kansas, United States of America., Shames SR; Division of Biology, Kansas State University, Manhattan, Kansas, United States of America.; Department of Microbiology & Molecular Genetics, Michigan State University, East Lansing, Michigan, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2023 Jun 22; Vol. 19 (6), pp. e1011473. Date of Electronic Publication: 2023 Jun 22 (Print Publication: 2023).
DOI: 10.1371/journal.ppat.1011473
Abstrakt: Legionella pneumophila is a natural pathogen of amoebae that causes Legionnaires' Disease in immunocompromised individuals via replication within macrophages. L. pneumophila virulence and intracellular replication hinges on hundreds of Dot/Icm-translocated effector proteins, which are essential for biogenesis of the replication-permissive Legionella-containing vacuole (LCV). However, effector activity can also enhance mammalian host defense via effector-triggered immunity. The L. pneumophila effector LegC4 is important for virulence in amoebae but enhances host defense against L. pneumophila in the mouse lung and, uniquely, within macrophages activated with either tumor necrosis factor (TNF) or interferon (IFN)-γ. The mechanism by which LegC4 potentiates cytokine-mediated host defense in macrophages is unknown. Here, we found that LegC4 enhances cytokine-mediated phagolysosomal fusion with Legionella-containing vacuole (LCV) and binds host proteasome activator (PA)28α, which forms a heterooligomer with PA28β to facilitate ubiquitin-independent proteasomal degradation of oxidant-damaged (carbonylated) proteins. We found that oxidative stress was sustained in the presence of LegC4 and that the LegC4 restriction phenotype was relieved in PA28αβ-deficient macrophages and in the lungs of mice in vivo. Our data also show that oxidative stress is sufficient for LegC4-mediated restriction in macrophages producing PA28αβ. PA28αβ has been traditionally associated with antigen presentation; however, our data support a novel mechanism whereby effector-mediated subversion of PA28αβ enhances cell-autonomous host defense against L. pneumophila under inflammatory and oxidative stress conditions. This work provides a solid foundation to evaluate induced proteasome regulators as mediators of innate immunity.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Ngwaga et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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