Legionella suppresses the host unfolded protein response via multiple mechanisms

Treacy-Abarca, Sean; Mukherjee, Shaeri

doi:10.1038/ncomms8887

Cited by 55 publications

(60 citation statements)

References 54 publications

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“…The ability of Legionella to inhibit UPR pathways, through bacterial proteins that inhibit protein synthesis, has been documented recently (40). Although that study showed that L. pneumophila could block chemically induced UPR pathways, our work points to the role of this inhibition in blocking bacterially induced UPR activation observed at late time points in cells challenged by the Δ5 strain.…”

Section: Discussioncontrasting

confidence: 40%

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

Hempstead

Isberg

2015

Proc. Natl. Acad. Sci. U.S.A.

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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

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Section: Discussioncontrasting

confidence: 40%

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

Hempstead

Isberg

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…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). …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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Summary All pathogens must acquire nutrients from their hosts. The intracellular bacterial pathogen Legionella pneumophila, the etiological agent of Legionnaires’ disease, requires host amino acids for growth within cells. The mechanistic target of rapamycin complex 1 (mTORC1) is an evolutionarily conserved master regulator of host amino acid metabolism. Here we identify two families of translocated L. pneumophila effector proteins that exhibit opposing effects on mTORC1 activity. The Legionella glucosyltransferase (Lgt) effector family activates mTORC1, through inhibition of host translation, whereas the SidE/SdeABC (SidE) effector family acts as mTORC1 inhibitors. We demonstrate that a common activity of both effector families is to inhibit host translation. We propose that the Lgt and SidE families of effectors work in concert to liberate host amino acids for consumption by L. pneumophila.

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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Orientia tsutsugamushi, an obligate intracellular bacterium that is auxotrophic for the aromatic amino acids and histidine, causes scrub typhus, a potentially deadly infection that threatens 1 billion people. O. tsutsugamushi growth is minimal during the first 24 to 48 h of infection but its growth becomes logarithmic thereafter. How the pathogen modulates cellular functions to support its growth is poorly understood. The unfolded protein response (UPR) is a cytoprotective pathway that relieves endoplasmic reticulum (ER) stress by promoting ER-associated degradation (ERAD) of misfolded proteins. Here, we show that O. tsutsugamushi invokes the UPR in the first 48 h and benefits from ER stress in an amino acid-dependent manner. O. tsutsugamushi also impedes ERAD during this time period. By 72 h, ER stress is alleviated and ERAD proceeds unhindered. Sustained inhibition of ERAD using RNA interference results in an O. tsutsugamushi growth defect at 72 h that can be rescued by amino acid supplementation. Thus, O. tsutsugamushi temporally stalls ERAD until ERAD-derived amino acids are needed to support its growth. The O. tsutsugamushi effector Ank4 is linked to this phenomenon. Ank4 interacts with Bat3, a eukaryotic chaperone that is essential for ERAD, and is transiently expressed by O. tsutsugamushi during the infection period when it inhibits ERAD. Ectopically expressed Ank4 blocks ERAD to phenocopy O. tsutsugamushi infection. Our data reveal a novel mechanism by which an obligate intracellular bacterial pathogen modulates ERAD to satisfy its nutritional virulence requirements.

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Legionella suppresses the host unfolded protein response via multiple mechanisms

Cited by 55 publications

References 54 publications

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

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

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

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

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