| First Author | Ngwaga T | Year | 2023 |
| Journal | PLoS Pathog | Volume | 19 |
| Issue | 6 | Pages | e1011473 |
| PubMed ID | 37347796 | Mgi Jnum | J:354250 |
| Mgi Id | MGI:7508600 | Doi | 10.1371/journal.ppat.1011473 |
| Citation | Ngwaga T, et al. (2023) Effector-mediated subversion of proteasome activator (PA)28alphabeta enhances host defense against Legionella pneumophila under inflammatory and oxidative stress conditions. PLoS Pathog 19(6):e1011473 |
| abstractText | 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)-gamma. 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)28alpha, which forms a heterooligomer with PA28beta 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 PA28alphabeta-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 PA28alphabeta. PA28alphabeta has been traditionally associated with antigen presentation; however, our data support a novel mechanism whereby effector-mediated subversion of PA28alphabeta 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. |
