Legionella pneumophilais a natural pathogen of amoebae that causes Legionnaires’ Disease in immunocompromised individuals via replication within macrophages.L.pneumophilavirulence and intracellular replication hinges on hundreds of Dot/Icm-translocated effector proteins, which are essential for biogenesis of the replication-permissiveLegionella-containing vacuole (LCV). However, effector activity can also enhance mammalian host defense via effector-triggered immunity. TheL.pneumophilaeffector LegC4 is important for virulence in amoebae but enhances host defense againstL.pneumophilain 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 withLegionella-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 micein 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 againstL.pneumophilaunder inflammatory and oxidative stress conditions. This work provides a solid foundation to evaluate induced proteasome regulators as mediators of innate immunity.