Dysregulation of Stress-Induced Translational Control by Porphyromonas gingivalis in Host Cells

KNOWLES, Alex A., CAMPBELL, Susan G., CROSS, Neil A. and STAFFORD, Prachi (2023). Dysregulation of Stress-Induced Translational Control by Porphyromonas gingivalis in Host Cells. Microorganisms, 11 (3): 6606.

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Abstract

Porphyromonas gingivalis contributes to the chronic oral disease periodontitis, triggering the activation of host inflammatory responses, inducing cellular stresses such as oxidation. During stress, host cells can activate the Integrated Stress Response (ISR), a pathway which determines cellular fate, by either downregulating protein synthesis and initiating a stress–response gene expression program, or by initiating programmed cell death. Recent studies have implicated the ISR within both host antimicrobial defenses and the pathomechanism of certain microbes. In this study, using a combination of immunofluorescence confocal microscopy and immunoblotting, the molecular mechanisms by which P. gingivalis infection alters translation attenuation during oxidative stress-induced activation of the ISR in oral epithelial cells were investigated. P. gingivalis infection alone did not result in ISR activation. In contrast, infection coupled with stress caused differential stress granule formation and composition. Infection heightened stress-induced translational repression independently of core ISR mediators. Heightened translational repression during stress was observed with both P. gingivalis–conditioned media and outer membrane vesicles, implicating a secretory factor in this exacerbated translational repression. The effects of gingipain inhibitors and gingipain-deficient P. gingivalis mutants confirmed these pathogen-specific proteases as the effector of exacerbated translational repression. Gingipains are known to degrade the mammalian target of rapamycin (mTOR) and the findings of this study implicate the gingipain-mTOR axis as the effector of host translational dysregulation during stress.

Item Type:	Article
Additional Information:	** Article version: VoR ** From MDPI via Jisc Publications Router ** Licence for VoR version of this article: https://creativecommons.org/licenses/by/4.0/ ** Peer reviewed: TRUE ** Acknowledgements: Acknowledgments: The authors would like to thank Tom Smith and Rachel Hodgson for fruitful discussions and Graham Stafford for the kind gift of the P. gingivalis gingipain null mutant strains. The authors would also like to gratefully acknowledge the Biomolecular Sciences Research Centre and Sheffield Hallam University, Sheffield, UK for funding this work. **Journal IDs: eissn 2076-2607 **Article IDs: publisher-id: microorganisms-11-00606 **History: collection 03-2023; published_online 27-02-2023; accepted 21-02-2023; rev-recd 15-02-2023; submitted 20-01-2023
Uncontrolled Keywords:	Article, Porphyromonas gingivalis, Integrated Stress Response, mTOR, gingipains
Identification Number:	https://doi.org/10.3390/microorganisms11030606
SWORD Depositor:	Colin Knott
Depositing User:	Colin Knott
Date Deposited:	07 Mar 2023 11:06
Last Modified:	07 Mar 2023 11:06
URI:	https://shura.shu.ac.uk/id/eprint/31621

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