Microbial Degradation of Cellular Kinases Impairs Innate Immune Signaling and Paracrine TNFα Responses

• Published in: Scientific reports 2016-10, Vol.6 (1), p.34656-34656, Article 34656
• Main Authors: Barth, Kenneth, Genco, Caroline Attardo
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/89; 13/95; 38/77; 49/90; 631/250/2161; 631/250/262; 631/250/516; 631/326/421; 82/29; 82/80; 96/21; Adhesins, Bacterial - genetics; Adhesins, Bacterial - immunology; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - immunology; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - immunology; Cytokines - genetics; Cytokines - immunology; Gene Expression Regulation; HEK293 Cells; HeLa Cells; Host-Pathogen Interactions - immunology; Human Umbilical Vein Endothelial Cells; Humanities and Social Sciences; Humans; Immunity, Innate; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - immunology; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - immunology; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - immunology; multidisciplinary; NF-kappa B - genetics; NF-kappa B - immunology; Paracrine Communication - immunology; Porphyromonas gingivalis - enzymology; Porphyromonas gingivalis - genetics; Porphyromonas gingivalis - pathogenicity; Proteolysis; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - immunology; Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - immunology; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Science; Signal Transduction; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep34656

The NFκB and MAPK signaling pathways are critical components of innate immunity that orchestrate appropriate immune responses to control and eradicate pathogens. Their activation results in the induction of proinflammatory mediators, such as TNFα a potent bioactive molecule commonly secreted by recruited inflammatory cells, allowing for paracrine signaling at the site of an infection. In this study we identified a novel mechanism by which the opportunistic pathogen Porphyromonas gingivalis dampens innate immune responses by disruption of kinase signaling and degradation of inflammatory mediators. The intracellular immune kinases RIPK1, TAK1, and AKT were selectively degraded by the P. gingivalis lysine-specific gingipain (Kgp) in human endothelial cells, which correlated with dysregulated innate immune signaling. Kgp was also observed to attenuate endothelial responsiveness to TNFα, resulting in a reduction in signal flux through AKT, ERK and NFκB pathways, as well as a decrease in downstream proinflammatory mRNA induction of cytokines, chemokines and adhesion molecules. A deficiency in Kgp activity negated decreases to host cell kinase protein levels and responsiveness to TNFα. Given the essential role of kinase signaling in immune responses, these findings highlight a unique mechanism of pathogen-induced immune dysregulation through inhibition of cell activation, paracrine signaling, and dampened cellular proinflammatory responses.