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- W4313407939 abstract "Abstract Macrophages activated by proinflammatory cytokines, such as tumor necrosis factor (TNF) and interferon (IFN)-γ, are potently and broadly microbicidal. Legionella pneumophila causes Legionnaires’ Disease via replication within host macrophages using an arsenal of hundreds of translocated virulence factors termed effector proteins. Effectors are critical for intracellular replication but can also enhance pathogen clearance in mammalian hosts via effector-triggered immunity. The effector LegC4 confers a fitness disadvantage on L. pneumophila in mouse models of Legionnaires’ Disease and uniquely potentiates the antimicrobial activity of macrophages activated with either TNF or IFN-γ. We found that LegC4 binds proteasome activator (PA)28α, a subunit of the PA28αβ (11S) proteasome regulator, and that the LegC4 restriction phenotype is abolished within PA28αβ-deficient macrophages. PA28αβ facilitates ubiquitin-independent proteasomal degradation of oxidant-damaged proteins. Impaired proteasome activity results in compensatory upregulation of lysosomal degradation pathways to relieve oxidative proteotoxic stress. We found that LegC4 impairs the resolution of oxidative proteotoxic stress and enhances phagolysosomal fusion with the Legionella-containing vacuole. PA28αβ has been traditionally associated with antigen presentation and adaptive immunity; however, our data support a model whereby suppression of PA28αβ by LegC4 impairs resolution of oxidative proteotoxic stress, which culminates in lysosomal killing of L. pneumophila within activated macrophages. This work provides a solid foundation on which to evaluate induced proteasome regulators as mediators of cell-autonomous immunity. This work is supported by NIH grant P20GM130448." @default.
- W4313407939 created "2023-01-06" @default.
- W4313407939 creator A5017930661 @default.
- W4313407939 date "2022-05-01" @default.
- W4313407939 modified "2023-10-16" @default.
- W4313407939 title "Effector-mediated subversion of proteasome activator (PA)28αβ enhances lysosomal pathogen targeting within cytokine-activated macrophages" @default.
- W4313407939 doi "https://doi.org/10.4049/jimmunol.208.supp.163.30" @default.
- W4313407939 hasPublicationYear "2022" @default.
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