Inhibition of host cell translation elongation by Legionella pneumophila blocks the host cell unfolded protein response

Abstract

Cells of the innate immune system recognize bacterial pathogens by detecting common microbial patterns as well as pathogenspecific activities. One system that responds to these stimuli is the IRE1 branch of the unfolded protein response (UPR), a sensor of endoplasmic reticulum (ER) stress. Activation of IRE1, in the context of Toll-like receptor (TLR) signaling, induces strong proinflammatory cytokine induction. We show here that Legionella pneumophila, an intravacuolar pathogen that replicates in an ER-associated compartment, blocks activation of the IRE1 pathway despite presenting pathogen products that stimulate this response. L. pneumophila TLR ligands induced the splicing of mRNA encoding XBP1s, the main target of IRE1 activity. L. pneumophila was able to inhibit both chemical and bacterial induction of XBP1 splicing via bacterial translocated proteins that interfere with host protein translation. A strain lacking five translocated translation elongation inhibitors was unable to block XBP1 splicing, but this could be rescued by expression of a single such inhibitor, consistent with limitation of the response by translation elongation inhibitors. Chemical inhibition of translation elongation blocked pattern recognition receptor-mediated XBP1 splicing, mimicking the effects of the bacterial translation inhibitors. In contrast, host cell-promoted inhibition of translation initiation in response to the pathogen was ineffective in blocking XBP1 splicing, demonstrating the need for the elongation inhibitors for protection from the UPR. The inhibition of host translation elongation may be a common strategy used by pathogens to limit the innate immune response by interfering with signaling via the UPR.Legionella | translation inhibition | unfolded protein response

Orientia tsutsugamushi Modulates Endoplasmic Reticulum-Associated Degradation To Benefit Its Growth

“…Unlike LegU1, Ank4 likely does not polyubiquitinate Bat3, as the apparent molecular weight and cellular level of Bat3 are unchanged in cells infected with O. tsutsugamushi compared to uninfected cells and in cells ectopically expressing Ank4 versus Ank4-ΔFbox. Rather than stimulate the UPR, L. pneumophila suppresses the UPR by multiple mechanisms, including blocking xbp1u splicing and inhibiting translation of BiP and CHOP (73,74). In addition to being a chaperone for ERAD, Bat3 regulates apoptosis, Hsp70 stability, and p53-related expression (75)(76)(77)(78).…”

Positive and Negative Regulation of the Master Metabolic Regulator mTORC1 by Two Families of Legionella pneumophila Effectors

“…Our data lead us to propose a speculative model for how L. pneumophila employs multiple effectors to inhibit mTORC1 and host protein synthesis—and thereby liberate host amino acids for bacterial consumption—without engaging autophagic responses that might restrict bacterial replication (Figure S4A). Of course, the effectors we identified have been shown to have diverse effects on cells, and it is therefore likely that mTORC1 modulation may only be a part of the complex biological roles of these effectors (Bhogaraju et al, 2016; Hempstead and Isberg, 2015; Kotewicz et al, 2017; Qiu et al, 2016; Treacy-Abarca and Mukherjee, 2015). …”

Host glycosylation pathways and the unfolded protein response contribute to the infection byFrancisella

“…L. monocytogenes requires UPR induction prior to host cell entry but not for invasion (Pillich et al, 2012). Finally, inhibition of the UPR, by the intracellular pathogens Simkania negevensis (Mehlitz et al, 2014) and Legionella (Treacy-Abarca and Mukherjee, 2015; Hempstead and isberg, 2015) have also been very recently described. Our data suggest that Francisella might also manipulate the UPR pathway to its advantage in infected macrophages.…”