Abstract
The intracellular pathogen, Legionella pneumophila, secretes ∼300 effector proteins to modulate the host environment. Given the intimate interaction between L. pneumophila and the endoplasmic reticulum, we investigated the role of the host unfolded protein response (UPR) during L. pneumophila infection. Interestingly, we show that the host identifies L. pneumophila infection as a form of endoplasmic reticulum stress and the sensor pATF6 is processed to generate pATF6(N), a transcriptional activator of downstream UPR genes. However, L. pneumophila is able to suppress the UPR and block the translation of prototypical UPR genes, BiP and CHOP. Furthermore, biochemical studies reveal that L. pneumophila uses two effectors (Lgt1 and Lgt2) to inhibit the splicing of XBP1u mRNA to spliced XBP1 (XBP1s), an UPR response regulator. Thus, we demonstrate that L. pneumophila is able to inhibit the UPR by multiple mechanisms including blocking XBP1u splicing and causing translational repression. This observation highlights the utility of L. pneumophila as a powerful tool for studying a critical protein homeostasis regulator.
Highlights
The intracellular pathogen, Legionella pneumophila, secretes B300 effector proteins to modulate the host environment
Given that L. pneumophila infections require recruitment of endoplasmic reticulum (ER)-derived vesicles to the Legionella-containing vacuole (LCV), yet infection does not perturb the ER morphology, we investigated whether L. pneumophila was able to suppress the unfolded protein response (UPR) during infection
An isogenic L. pneumophila strain, DdotA, which lacks a functional type IV secretion system, was unable to suppress the upregulation of BiP or C/EBP homologous protein (CHOP) in the presence of thapsigargin, indicating that this suppression is dependent on secreted effectors
Summary
The intracellular pathogen, Legionella pneumophila, secretes B300 effector proteins to modulate the host environment. We demonstrate that L. pneumophila is able to inhibit the UPR by multiple mechanisms including blocking XBP1u splicing and causing translational repression. This observation highlights the utility of L. pneumophila as a powerful tool for studying a critical protein homeostasis regulator. L. pneumophila actively utilizes an arsenal of B300 secreted bacterial effectors to modulate cellular pathways during infection to provide the pathogen optimal conditions for replication. The secreted effectors enable L. pneumophila to manipulate key cellular pathways such as protein trafficking, autophagy, immune response and host chromatin remodelling among others[1,2]. Given the close interaction between L. pneumophila and the ER, we found this question intriguing
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