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Dysregulation of stress-induced translational control by Porphyromonas gingivalis in host cells

Alex A Knowles, Susan G Campbell, Neil A Cross, View ORCID ProfilePrachi Stafford
doi: https://doi.org/10.1101/2022.01.24.477647
Alex A Knowles
1Biomolecular Sciences Research Centre, Department of Biosciences and Chemistry, Faculty of Health and Wellbeing, Sheffield Hallam University, Sheffield, UK
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Susan G Campbell
1Biomolecular Sciences Research Centre, Department of Biosciences and Chemistry, Faculty of Health and Wellbeing, Sheffield Hallam University, Sheffield, UK
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Neil A Cross
1Biomolecular Sciences Research Centre, Department of Biosciences and Chemistry, Faculty of Health and Wellbeing, Sheffield Hallam University, Sheffield, UK
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Prachi Stafford
1Biomolecular Sciences Research Centre, Department of Biosciences and Chemistry, Faculty of Health and Wellbeing, Sheffield Hallam University, Sheffield, UK
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  • ORCID record for Prachi Stafford
  • For correspondence: p.stafford@shu.ac.uk
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ABSTRACT

Periodontitis, a chronic inflammatory gum disease, is caused in part by the periodontopathogen Porphyromonas gingivalis. Infection triggers activation of host inflammatory responses which induce stresses such as oxidative stress. Under such conditions, cells can activate the Integrated Stress Response (ISR), a signalling cascade which functions to determine cellular fate, by either downregulating protein synthesis and initiating a stress-response gene expression program, or if stress cannot be overcome, initiating programmed cell death. Recent studies have implicated the ISR signalling in both host antimicrobial defences and within the pathomechanism of certain microbes.

In this study, we investigated how P. gingivalis infection alters translation attenuation during oxidative stress-induced activation of the ISR pathway in oral epithelial cells. P. gingivalis infection alone did not result in ISR activation. In contrast, infection coupled with stress led to differential stress granule formation and composition, along with dysregulation of the microtubule network. Infection also heightened stress-induced translational repression, a response which could not be rescued by ISRIB, a potent ISR inhibitor. Heightened translational repression during stress was observed with both P. gingivalis conditioned media and outer membrane vesicles, implicating the role of a secretory factor, probably proteases known as gingipains, in this exacerbated translational repression. The effects of gingipain inhibitors and gingipains-deficient P. gingivalis mutants further confirmed these pathogen-specific proteases as the effector.

Gingipains are known to degrade the mammalian target of rapamycin (mTOR) and these studies implicate the gingipain-mTOR axis as the effector of host translational dysregulation during stress.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 26, 2022.
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Dysregulation of stress-induced translational control by Porphyromonas gingivalis in host cells
Alex A Knowles, Susan G Campbell, Neil A Cross, Prachi Stafford
bioRxiv 2022.01.24.477647; doi: https://doi.org/10.1101/2022.01.24.477647
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Dysregulation of stress-induced translational control by Porphyromonas gingivalis in host cells
Alex A Knowles, Susan G Campbell, Neil A Cross, Prachi Stafford
bioRxiv 2022.01.24.477647; doi: https://doi.org/10.1101/2022.01.24.477647

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