The Role of Glutamine Metabolism for P. gingivalis-Induced Non-Canonical Autophagy in Epithelial Cells

谷氨酰胺代谢对牙龈卟啉单胞菌诱导的上皮细胞非典型自噬的作用

• 批准号: 10537625
• 负责人: Bridgette Frances Wellslager
• 金额: $ 4.76万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537625
• 关键词: Affect; Amino Acids; Anaerobic Bacteria; Antioxidants; Autophagocytosis; Autophagosome; Bacteria; Biogenesis; Biology; Cell physiology; Cells; Chronic; Chronic Disease; Complex; Coupling; Critical Pathways; Data; Degradation Pathway; Dependence; Development; Disease; Elements; Endoplasmic Reticulum; Environment; Epithelial; Epithelial Cells; Event; Fellowship; Fostering; Foundations; GTP-Binding Protein alpha Subunits, Gs; Gene Proteins; Generations; Gingiva; Glutamine; Glutathione; Goals; Homeostasis; Human; Immune; Impairment; Infection; Knowledge; Life; Lipids; Maintenance; Mediating; Membrane; Metabolic; Metabolic Pathway; Metabolism; Microtubule-Associated Proteins; Molecular; Mucous Membrane; Oral; Oral cavity; Oral health; Oral mucous membrane structure; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Periodontitis; Porphyromonas gingivalis; Production; Protein Isoforms; Publishing; Recycling; Regulation; Research; Role; Route; Scientist; Secure; Testing; Time; Training; Ultraviolet Rays; Vacuole; Variant; amino acid metabolism; antimicrobial; cellular pathology; combat; dysbiosis; glutathione peroxidase; microbial; microorganism; molecular phenotype; new therapeutic target; novel; novel therapeutics; oral biology; pathobiont; pathogen; radiation resistance; recruit; therapeutically effective

Growing evidence underlines that Glutamine (Gln) metabolism can influence key metabolic and autophagic cellular events. Porphyromonas gingivalis (P.g) is a major periodontopathic, fastidious, pathobiont and successful colonizer of gingival mucosa, which has recently been identified to induce a special form of autophagy in human gingival epithelial cells (GECs). While GECs function as an intrinsically important first line of immune defense of the gingiva, GECs can be exploited by P.g for securing a successful persistence niche in the oral mucosa and a potential systemic dissemination route. Despite the growing evidence pinpointing that altered Gln metabolism can contribute to cellular pathologies, knowledge gaps remain regarding how host Gln metabolism could be influenced by bacteria to regulate host redox homeostasis and potentially promote bacterial survival in the GECs. Recently, we discovered that P.g steadily increases robust Glutathione (GSH) production in GECs to combat host-mediated oxidative stress-driven pathogen clearance. Our novel findings, for the first time, show that P.g infection alters host Gln metabolism, a component of GSH synthesis, in GECs. In addition, we recently demonstrated that P.g induces a pro-bacterial form of autophagy in GECs, where Endoplasmic Reticulum-rich (ER)/Microtubule-associated protein 1A/1B-light chain 3 (LC3) double membrane autophagosomes act as replicative niches for P.g and protect the bacteria from antimicrobial degradation pathways. Our novel data shows that the biogenesis and maintenance of these P.g-containing autophagosomes is dependent on the critical redox molecule, Glutathione Peroxidase 1 (GpX1). The dependency on GpX1 can be markedly altered by increasing free Gln levels in GECs' cellular environment. Thus, our overarching hypothesis for this proposal is that P.g alters host Gln metabolism in GECs to maintain host redox homeostasis and specifically contributes to the biogenesis of a GpX1-driven, pro-bacterial form of autophagy. Two Specific Aims are proposed to test this hypothesis. Aim 1 will characterize the phenotypic molecular events occurring during P.g infection that specifically associate with host cell Gln metabolism and the host cell redox state, allowing for the intracellular survival of P.g in GECs. Aim 2 will mechanistically determine the molecular interactome involved in P.g-induced autophagy through the modulation of host Gln metabolism in GECs. These collectively will identify what elements of the Gln metabolic pathways are critical for the autophagic survival of P.g in GECs, and will elucidate the specific molecular machineries involved in pro-bacterial autophagy driven by changes in host Gln metabolism upon P.g infection. Overall, this proposal will contribute to the identification of novel targeted therapeutic strategies to control the chronic intracellular colonization of P.g in the oral mucosa and beyond. Receiving the F31 Fellowship for this proposal will further the applicant's research goals, critically contribute to her training in the field of Oral Biology, and will foster her unique development as an oral health academic scientist.

越来越多的证据表明，谷氨酰胺（Gln）代谢可以影响关键的代谢和自噬